Brain pathology in myotonic dystrophy: When tauopathy meets spliceopathy and RNAopathy

Frontiers in Molecular Neuroscience

Volumn 6, Issue JAN, 2014, Pages

  Caillet Boudin, Marie Laure ^a,b   Fernandez Gomez, Francisco Jose ^a,b   Tran, Hélène ^a,b,c   Dhaenens, Claire Marie ^a,b   Buee, Luc ^a,b   Sergeant, Nicolas ^a,b  

^a JEAN PIERRE AUBERT RESEARCH CENTER   (France)

^b UNIV LILLE   (France)

^c UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

Author keywords

Alzheimer's disease; Myotonic dystrophy; RNAopathy; Splicing; Tauopathy

Indexed keywords

EID: 84892573930     PISSN: 16625099     EISSN: None     Source Type: Journal    
DOI: 10.3389/fnmol.2013.00057     Document Type: Review

References (304)

1. Abraham, R., Sims, R., Carroll, L., Hollingworth, P., O'Donovan, M. C., Williams, J., et al. (2009). An association study of common variation at the MAPT locus with late-onset Alzheimer's disease. Am. J. Med. Genet. B Neuropsychiatr. Genet. 150B, 1152-1155. doi: 10.1002/ajmg.b.30951
2. Alonso, A., Zaidi, T., Novak, M., Grundke-Iqbal, I., and Iqbal, K. (2001). Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc. Natl. Acad. Sci. U.S.A. 98, 6923-6928. doi: 10.1073/pnas.121119298
3. Amadoro, G., Ciotti, M. T., Costanzi, M., Cestari, V., Calissano, P., and Canu, N. (2006). NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation. Proc. Natl. Acad. Sci. U.S.A. 103, 2892-2897. doi: 10.1073/pnas.0511065103
4. Amador-Ortiz, C., Lin, W. L., Ahmed, Z., Personett, D., Davies, P., Duara, R., et al. (2007). TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease. Ann. Neurol. 61, 435-445. doi: 10.1002/ana.21154
5. Anderson, C. M., Henry, R. R., Knudson, P. E., Olefsky, J. M., and Webster, N. J. (1993). Relative expression of insulin receptor isoforms does not differ in lean, obese, and noninsulin-dependent diabetes mellitus subjects. J. Clin. Endocrinol. Metab. 76, 1380-1382. doi: 10.1210/jc.76.5.1380
6. Andreadis, A. (2005). Tau gene alternative splicing: expression patterns, regulation and modulation of function in normal brain and neurodegenerative diseases. Biochim. Biophys. Acta 1739, 91-103. doi: 10.1016/j.bbadis.2004.08.010
7. Antonini, G., Mainero, C., Romano, A., Giubilei, F., Ceschin, V., Gragnani, F., et al. (2004). Cerebral atrophy in myotonic dystrophy: a voxel based morphometric study. J. Neurol. Neurosurg. Psychiatr. 75, 1611-1613. doi: 10.1136/jnnp.2003.032417
8. Antonini, G., Soscia, F., Giubilei, F., De Carolis, A., Gragnani, F., and Morino, S. (2006). Health-related quality of life in myotonic dystrophy type 1 and its relationship with cognitive and emotional functioning. J. Rehabil. Med. 38, 181-185. doi: 10.1080/16501970500477967
9. Arikan, M. C., Memmott, J., Broderick, J. A., Lafyatis, R., Screaton, G., Stamm, S., et al. (2002). Modulation of the membrane-binding projection domain of tau protein: splicing regulation of exon 3. Brain Res. Mol. Brain Res. 101, 109-121. doi: 10.1016/S0169-328X(02)00178-X
10. Axford, M. M., and Pearson, C. E. (2013). Illuminating CNS and cognitive issues in myotonic dystrophy: Workshop report. Neuromuscul. Disord. 23, 370-374. doi: 10.1016/j.nmd.2013.01.003
11. Bai, B., Hales, C. M., Chen, P. C., Gozal, Y., Dammer, E. B., Fritz, J. J., et al. (2013). U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. 110, 16562-16567. doi: 10.1073/pnas.13102 49110
12. Baig, S., van Helmond, Z., and Love, S. (2009). Tau hyperphosphory-lation affects Smad 2/3 translocation. Neuroscience 163, 561-570. doi: 10.1016/j.neuroscience.2009.06.045
13. Baker, M., Graff-Radford, D., Wavrant DeVrieze, F., Graff-Radford, N., Petersen, R. C., Kokmen, E., et al. (2000). No association between TAU haplotype and Alzheimer's disease in population or clinic based series or in familial disease. Neurosci. Lett. 285, 147-149. doi: 10.1016/S0304-3940(00)01057-0
14. Ball, M. J. (1977). Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia. A quantitative study. Acta Neuropathol. 37, 111-118. doi: 10.1007/BF00692056
15. Ball, M. J., and Lo, P. (1977). Granulovacuolar degeneration in the ageing brain and in dementia. J. Neuropathol. Exp. Neurol. 36, 474-487. doi: 10.1097/00005072-197705000-00006
16. Barnby, G., Abbott, A., Sykes, N., Morris, A., Weeks, D. E., Mott, R., et al. (2005). Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT. Am. J. Hum. Genet. 76, 950-966. doi: 10.1086/430454
17. Batra, R., Charizanis, K., and Swanson, M. S. (2010). Partners in crime: bidirectional transcription in unstable microsatellite disease. Hum. Mol. Genet. 19, R77-R82. doi: 10.1093/hmg/ddq132
18. Belfiore, A., Frasca, F., Pandini, G., Sciacca, L., and Vigneri, R. (2009). Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr. Rev. 30, 586-623. doi: 10.1210/er. 2008-0047
19. Benecke, H., Flier, J. S., and Moller, D. E. (1992). Alternatively spliced variants of the insulin receptor protein. Expression in normal and diabetic human tissues. J. Clin. Invest. 89, 2066-2070. doi: 10.1172/JCI115819
20. Bennett, D. A., Schneider, J. A., Wilson, R. S., Bienias, J. L., and Arnold, S. E. (2004). Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Arch. Neurol 61, 378-384. doi: 10.1001/archneur.61.3.378
21. Berg, L., Mckeel, D. W. Jr., Miller, J. P., Storandt, M., Rubin, E. H., Morris, J. C, et al. (1998). Clinicopathologic studies in cognitively healthy aging and Alzheimer's disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch. Neurol 55, 326-335. doi: 10.1001/arch-neur.55.3.326
22. Berson, A., Barbash, S., Shaltiel, G., Goll, Y., Hanin, G., Greenberg, D. S., et al. (2012). Cholinergic-associated loss of hnRNP-A/B in Alzheimer's disease impairs cortical splicing and cognitive function in mice. EMBO Mol. Med. 4, 730-742. doi: 10.1002/emmm.201100995
23. Bhalla, K., Phillips, H. A., Crawford, J., McKenzie, O. L., Mulley, J. C., Eyre, H., et al. (2004). The de novo chromosome 16 translocations of two patients with abnormal phenotypes (mental retardation and epilepsy) disrupt the A2BP1 gene. /. Hum. Genet. 49, 308-311. doi: 10.1007/s10038-004-0145-4
24. Bieniek, K. F., Murray, M. E., Rutherford, N. J., Castanedes-Casey, M., DeJesus-Hernandez, M., Liesinger, A. M., et al. (2013). Tau pathology in frontotempo-ral lobar degeneration with C9ORF72 hexanucleotide repeat expansion. Ada Neuropathol 125, 289-302. doi: 10.1007/s00401-012-1048-7
25. Bitel, C. L., Kasinathan, C., Kaswala, R. H., Klein, W. L., and Frederikse, P. H. (2012). Amyloid-beta and tau pathology of Alzheimer's disease induced by diabetes in a rabbit animal model. /. Alzheimers. Dis. 32, 291-305. doi: 10.3233/JAD-2012-120571
26. Blennow, K., and Hampel, H. (2003). CSF markers for incipient Alzheimer's disease. Lancet Neurol 2, 605-613. doi: 10.1016/S1474-4422(03)00530-1
27. Bombois, S., Duhamel, A., Salleron, J., Deramecourt, V., Mackowiak, M. A., Deken, V., et al. (2013). A new decision tree combining Abeta 1-42 and p-Tau levels in Alzheimer's diagnosis. Curr. Alzheimer Res. 10, 357-364. doi: 10.2174/1567205011310040002
28. Bosco, D., Fava, A., Plastino, M., Montalcini, T., and Pujia, A. (2011). Possible implications of insulin resistance and glucose metabolism in Alzheimer's disease pathogenesis. /. Cell Mol Med. 15, 1807-1821. doi: 10.1111/j.1582-4934.2011.01318.x
29. Bose, J. K., Wang, I. F., Hung, L., Tarn, W. Y., and Shen, C. K. (2008). TDP-43 over-expression enhances exon 7 inclusion during the survival of motor neuron pre-mRNA splicing./. Biol Chem. 283, 28852-28859. doi: 10.1074/jbc.M805376200
30. Boutajangout, A., Boom, A., Leroy, K., and Brion, J. P. (2004). Expression of tau mRNA and soluble tau isoforms in affected and non-affected brain areas in Alzheimer's disease. FEBS Lett. 576, 183-189. doi: 10.1016/j.febslet.2004.09.011
31. Braak, H., and Braak, E. (1991). Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82, 239-259. doi: 10.1007/BF00308809
32. ; end of a transcript encoding a protein kinase family member. Cell 68, 799-808. doi: 10.1016/0092-8674(92)90154-5
33. Bruehl, H., Sweat, V., Hassenstab, J., Polyakov, V., and Convit, A. (2010). Cognitive impairment in nondiabetic middle-aged and older adults is associated with insulin resistance. /. Clin. Exp. Neuropsychol 32, 487-493. doi: 10.1080/13803390903224928
34. Buee, L., Troquier, L., Burnouf, S., Belarbi, K., Van Der Jeugd, A., Ahmed, T., et al. (2010). From tau phosphorylation to tau aggregation: what about neuronal death? Biochem. Soc. Trans. 38, 967-972. doi: 10.1042/BST0380967
35. Bungener, C, Jouvent, R., and Delaporte, C. (1998). Psychopathological and emotional deficits in myotonic dystrophy. Neurol. Neurosurg. Psychiatr. 65, 353-356. doi: 10.1136/jnnp.65.3.353
36. Bunker, J. M., Wilson, L., Jordan, M. A., and Feinstein, S. C. (2004). Modulation of microtubule dynamics by tau in living cells: implications for development and neurodegeneration. Mol. Biol. Cell 15, 2720-2728. doi: 10.1091/mbc.E04-01-0062
37. Buratti, E., Brindisi, A., Giombi, M., Tisminetzky, S., Ayala, Y M., and Baralle, F. E. (2005). TDP-43 binds heterogeneous nuclear ribonucleoprotein A/B through its C-terminal tail: an important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon 9 splicing. /. Biol. Chem. 280, 37572-37584. doi: 10.1074/jbc.M505557200
38. Caffrey, T. M., Joachim, C, and Wade-Martins, R. (2008). Haplotype-specific expression of the N-terminal exons 2 and 3 at the human MAPT locus. Neurobiol. Aging 29, 1923-1929. doi: 10.1016/j.neurobiolaging.2007.05.002
39. Caillierez, R., Begard, S., Lecolle, K., Deramecourt, V., Zommer, N., Dujardin, S., et al. (2013). Lentiviral delivery of the human wild-type tau protein mediates a slow and progressive neurodegenerative tau pathology in the rat brain. Mol. Ther. 21, 1358-1368. doi: 10.1038/mt.2013.66
40. Carrasquillo, M. M., Belbin, O., Hunter, T. A., Ma, L., Bisceglio, G. D., Zou, F., et al. (2011). Replication of BIN1 association with Alzheimer's disease and evaluation of genetic interactions. J. Alzheimers. Dis. 24, 751-758. doi: 10.3233/JAD-2011-101932
41. Censori, B., Provinciali, L., Danni, M., Chiaramoni, L., Maricotti, M., Foschi, N., et al. (1994). Brain involvement in myotonic dystrophy: MRI features and their relationship to clinical and cognitive conditions. Acta Neurol. Scand. 90, 211-217. doi: 10.1111/j.1600-0404.1994.tb02708.x
42. Chandler, L. J., Harris, R. A., and Crews, F. T. (1998). Ethanol tolerance and synaptic plasticity. Trends Pharmacol. Sci. 19, 491-495. doi: 10.1016/S0165-6147(98)01268-1
43. Chapuis, J., Hansmannel, F., Gistelinck, M., Mounier, A., Van Cauwenberghe, C., Kolen, K. V., et al. (2013). Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol. Psychiatry 18, 1225-1234. doi: 10.1038/mp.2013.1
44. Charizanis, K., Lee, K. Y., Batra, R., Goodwin, M., Zhang, C., Yuan, Y., et al. (2012). Muscleblind-like 2-mediated alternative splicing in the developing brain and dysregulation in myotonic dystrophy. Neuron 75, 437-450. doi: 10.1016/j.neuron.2012.05.029
45. Charlet-B. N., Savkur, R. S., Singh, G., Philips, A. V., Grice, E. A., and Cooper, T. A. (2002). Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol. Cell 10, 45-53. doi: 10.1016/S1097-2765(02)00572-5
46. Cho, D. H., and Tapscott, S. J. (2007). Myotonic dystrophy: emerging mechanisms for DM1 and DM2. Biochim. Biophys. Acta 1772, 195-204. doi: 10.1016/j.bbadis.2006.05.013
47. Clavaguera, F., Akatsu, H., Fraser, G., Crowther, R. A., Frank, S., Hench, J., et al. (2013). Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc. Natl. Acad. Sci. U.S.A. 110, 9535-9540. doi: 10.1073/pnas.1301175110
48. Clavaguera, F., Bolmont, T., Crowther, R. A., Abramowski, D., Frank, S., Probst, A., et al. (2009). Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11, 909-913. doi: 10.1038/ncb1901
49. Cohen, O. S., McCoy, S. Y., Middleton, F. A., Bialosuknia, S., Zhang-James, Y., Liu, L., et al. (2012). Transcriptomic analysis of postmortem brain identifies dysreg-ulated splicing events in novel candidate genes for schizophrenia. Schizophr. Res. 142, 188-199. doi: 10.1016/j.schres.2012.09.015
50. Combs, B., Voss, K., and Gamblin, T. C. (2011). Pseudohyperphosphorylation has differential effects on polymerization and function of tau isoforms. Biochemistry 50, 9446-9456. doi: 10.1021/bi2010569
51. Connell, J. W., Rodriguez-Martin, T., Gibb, G. M., Kahn, N. M., Grierson, A. J., Hanger, D. P., et al. (2005). Quantitative analysis of tau isoform transcripts in sporadic tauopathies. Brain Res. Mol. Brain Res. 137, 104-109. doi: 10.1016/j.molbrainres.2005.02.014
52. Conrad, C., Zhu, J., Schoenfeld, D., Fang, Z., Ingelsson, M., Stamm, S., et al. (2007). Single molecule profiling of tau gene expression in Alzheimer's disease. J. Neurochem. 103, 1228-1236. doi: 10.1111/j.1471-4159.2007.04857.x
53. Cooper-Knock, J., Kirby, J., Ferraiuolo, L., Heath, P. R., Rattray, M., and Shaw, P. J. (2012). Gene expression profiling in human neurodegenerative disease. Nat. Rev. Neurol. 8, 518-530. doi: 10.1038/nrneurol.2012.156
54. Couchie, D., Mavilia, C., Georgieff, I. S., Liem, R. K., Shelanski, M. L., and Nunez, J. (1992). Primary structure of high molecular weight tau present in the peripheral nervous system. Proc. Natl. Acad. Sci. U.S.A. 89, 4378-4381. doi: 10.1073/pnas.89.10.4378
55. Cowan, C. M., and Mudher, A. (2013). Are tau aggregates toxic or protective in tauopathies? Front. Neurol. 4:114. doi: 10.3389/fneur.2013.00114
56. D'Angelo, M. G., and Bresolin, N. (2003). Report of the 95th European Neuromuscular Centre (ENMC) sponsored international workshop cognitive impairment in neuromuscular disorders, Naarden, The Netherlands 13-15 July 2001. Neuromuscul. Disord. 13, 72-79. doi: 10.1016/S0960-8966(02)00155-4
57. Day, J. W., and Ranum, L. P. (2005). RNA pathogenesis of the myotonic dystrophies. Neuromuscul. Disord. 15, 5-16. doi: 10.1016/j.nmd.2004.09.012
58. De Calignon, A., Polydoro, M., Suarez-Calvet, M., William, C., Adamowicz, D. H., Kopeikina, K. J., et al. (2012). Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73, 685-697. doi: 10.1016/j.neuron.2011.11.033
59. De Felice, F. G., Velasco, P. T., Lambert, M. P., Viola, K., Fernandez, S. J., Ferreira, S. T., et al. (2007). Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J. Biol. Chem. 282, 11590-11601. doi: 10.1074/jbc.M607483200
60. DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., et al. (2011). Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245-256. doi: 10.1016/j.neuron.2011.09.011
61. Delacourte, A., David, J. P., Sergeant, N., Buee, L., Wattez, A., Vermersch, P., et al. (1999). The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease. Neurology 52, 1158-1165. doi: 10.1212/WNL.52.6.1158
62. de Mezer, M., Wojciechowska, M., Napierala, M., Sobczak, K., and Krzyzosiak, W. J. (2011). Mutant CAG repeats of Huntingtin transcript fold into hairpins, form nuclear foci and are targets for RNA interference. Nucleic Acids Res. 39, 3852-3863. doi: 10.1093/nar/gkq1323
63. Dhaenens, C. M., Schraen-Maschke, S., Tran, H., Vingtdeux, V., Ghanem, D., Leroy, O., et al. (2008). Overexpression of MBNL1 fetal isoforms and modified splicing of Tau in the DM1 brain: two individual consequences of CUG trinucleotide repeats. Exp. Neurol. 210, 467-478. doi: 10.1016/j.expneurol.2007.11.020
64. Dhaenens, C. M., Tran, H., Frandemiche, M. L., Carpentier, C., Schraen-Maschke, S., Sistiaga, A., et al. (2011). Mis-splicing of Tau exon 10 in myotonic dystrophy type 1 is reproduced by overexpression of CELF2 but not by MBNL1 silencing. Biochim. Biophys. Acta 1812, 732-742. doi: 10.1016/j.bbadis.2011.03.010
65. Di Costanzo, A., Di Salle, F., Santoro, L., Bonavita, V., and Tedeschi, G., (2001) Dilated Virchow-Robin spaces in myotonic dystrophy: frequency, extent and significance. Eur. Neurol. 46, 131-139. doi: 10.1159/000050786
66. Dixit, R., Ross, J. L., Goldman, Y. E., and Holzbaur, E. L. (2008). Differential regulation of dynein and kinesin motor proteins by tau. Science 319, 1086-1089. doi: 10.1126/science.1152993
67. Dominguez, E., Chin, T. Y., Chen, C. P., and Wu, T. Y. (2011). Management of moderate to severe Alzheimer's disease: focus on memantine. Taiwan. J. Obstet. Gynecol. 50, 415-423. doi: 10.1016/j.tjog.2011.10.004
68. Donev, R., Kolev, M., Millet, B., and Thome, J. (2009). Neuronal death in Alzheimer's disease and therapeutic opportunities. J. Cell. Mol. Med. 13, 4329-4348. doi: 10.1111/j.1582-4934.2009.00889.x
69. Dou, F., Netzer, W. J., Tanemura, K., Li, F., Hartl, F. U., Takashima, A., et al. (2003). Chaperones increase association of tau protein with microtubules. Proc. Natl. Acad. Sci. U.S.A. 100, 721-726. doi: 10.1073/pnas.242720499
70. Dreumont, N., Hardy, S., Behm-Ansmant, I., Kister, L., Branlant, C., Stevenin, J., et al. (2010). Antagonistic factors control the unproductive splicing of SC35 terminal intron. Nucleic Acids Res. 38, 1353-1366. doi: 10.1093/nar/gkp1086
71. Duyckaerts, C., Bennecib, M., Grignon, Y., Uchihara, T., He, Y., Piette, F., et al. (1997). Modeling the relation between neurofibrillary tangles and intellectual status. Neurobiol. Aging 18, 267-273. doi: 10.1016/S0197-4580(97)80306-5
72. Echavarri, C., Burgmans, S., Caballero, M. C., Garcia-Bragado, F., Verhey, F. R., and Uylings, H. B. (2012). Co-occurrence of different pathologies in dementia: implications for dementia diagnosis. J. Alzheimers. Dis. 30, 909-917. doi: 10.3233/JAD-2012-111400
73. Ekstrom, A. B., Hakenas-Plate, L., Samuelsson, L., Tulinius, M., and Wentz, E. (2008). Autism spectrum conditions in myotonic dystrophy type 1: a study on 57 individuals with congenital and childhood forms. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B, 918-926. doi: 10.1002/ajmg.b.30698
74. Fallini, C., Bassell, G. J., and Rossoll, W. (2012). The ALS disease protein TDP-43 is actively transported in motor neuron axons and regulates axon outgrowth. Hum. Mol. Genet. 21, 3703-3718. doi: 10.1093/hmg/dds205
75. Fardaei, M., Larkin, K., Brook, J. D., and Hamshere, M. G. (2001). In vivo co-localisation of MBNL protein with DMPK expanded-repeat transcripts. Nucleic Acids Res. 29, 2766-2771. doi: 10.1093/nar/29.13.2766
76. Fardaei, M., Rogers, M. T., Thorpe, H. M., Larkin, K., Hamshere, M. G., Harper, P. S., et al. (2002). Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells. Hum. Mol. Genet. 11, 805-814. doi: 10.1093/hmg/11.7.805
77. Feng, D., and Xie, J. (2013). Aberrant splicing in neurological diseases. Wiley Interdiscip. Rev. RNA 4, 631-649. doi: 10.1002/wrna.1184
78. Fiesel, F. C., Weber, S. S., Supper, J., Zell, A., and Kahle, P. J. (2012). TDP-43 regulates global translational yield by splicing of exon junction complex component SKAR. Nucleic Acids Res. 40, 2668-2682. doi: 10.1093/nar/gkr1082
79. Freibaum, B. D., Chitta, R. K., High, A. A., and Taylor, J. P. (2010). Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. J. Proteome Res. 9, 1104-1120. doi: 10.1021/pr901076y
80. Frisardi, V., Solfrizzi, V., Seripa, D., Capurso, C., Santamato, A., Sancarlo, D., et al. (2010). Metabolic-cognitive syndrome: a cross-talk between metabolic syndrome and Alzheimer's disease. Ageing Res. Rev. 9, 399-417. doi: 10.1016/j.arr.2010.04.007
81. Fu, Y. H., Friedman, D. L., Richards, S., Pearlman, J. A., Gibbs, R. A., Pizzuti, A., et al. (1993). Decreased expression of myotonin-protein kinase messenger RNA and protein in adult form of myotonic dystrophy. Science 260, 235-238. doi: 10.1126/science.8469976
82. Fugier, C., Klein, A. F., Hammer, C., Vassilopoulos, S., Ivarsson, Y., Toussaint, A., et al. (2011). Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy. Nat. Med. 17, 720-725. doi: 10.1038/nm.2374
83. Fukuda, H., Horiguchi, J., Ono, C., Ohshita, T., Takaba, J., and Ito, K. (2005). Diffusion tensor imaging of cerebral white matter in patients with myotonic dystrophy. Acta Radiol. 46, 104-109. doi: 10.1080/02841850510015974
84. Funk, K. E., Mrak, R. E., and Kuret, J. (2011). Granulovacuolar degeneration (GVD) bodies of Alzheimer's disease (AD) resemble late-stage autophagic organelles. Neuropathol. Appl. Neurobiol. 37, 295-306. doi: 10.1111/j.1365-2990.2010.01135.x
85. Garcia-Murias, M., Quintans, B., Arias, M., Seixas, A. I., Cacheiro, P., Tarrio, R., et al. (2012). "Costa da Morte" ataxia is spinocerebellar ataxia 36: clinical and genetic characterization. Brain 135, 1423-1435. doi: 10.1093/brain/aws069
86. Georgieff, I. S., Liem, R. K., Couchie, D., Mavilia, C., Nunez, J., and Shelanski, M. L. (1993). Expression of high molecular weight tau in the central and peripheral nervous systems. J. Cell Sci. 105(Pt 3), 729-737.
87. Ghoshal, N., Garcia-Sierra, F., Wuu, J., Leurgans, S., Bennett, D. A., Berry, R. W., et al. (2002). Tau conformational changes correspond to impairments of episodic memory in mild cognitive impairment and Alzheimer's disease. Exp. Neurol. 177, 475-493. doi: 10.1006/exnr.2002.8014
88. Giannakopoulos, P., Herrmann, F. R., Bussiere, T., Bouras, C., Kovari, E., Perl, D. P., et al. (2003). Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's disease. Neurology 60, 1495-1500. doi: 10.1212/01.WNL.0000063311.58879.01
89. Gibb, W. R., Mountjoy, C. Q., Mann, D. M., and Lees, A. J. (1989). A pathological study of the association between Lewy body disease and Alzheimer's disease. J. Neurol. Neurosurg. Psychiatr. 52, 701-708. doi: 10.1136/jnnp.52.6.701
90. Glatz, D. C., Rujescu, D., Tang, Y., Berendt, F. J., Hartmann, A. M., Faltraco, F., et al. (2006). The alternative splicing of tau exon 10 and its regulatory proteins CLK2 and TRA2-BETA1 changes in sporadic Alzheimer's disease. J. Neurochem. 96, 635-644. doi: 10.1111/j.1471-4159.2005.03552.x
91. Gomes-Pereira, M., Foiry, L., Nicole, A., Huguet, A., Junien, C., Munnich, A., et al. (2007). CTG trinucleotide repeat "big jumps": large expansions, small mice. PLoS Genet. 3:e52. doi: 10.1371/journal.pgen.0030052
92. Goode, B. L., and Feinstein, S. C. (1994). Identification of a novel microtubule binding and assembly domain in the developmentally regulated inter-repeat region of tau. J. Cell Biol. 124, 769-782. doi: 10.1083/jcb.124.5.769
93. Hansen, T., Bjorbaek, C., Vestergaard, H., Gronskov, K., Bak, J. F., and Pedersen, O. (1993). Expression of insulin receptor spliced variants and their functional correlates in muscle from patients with non-insulin-dependent diabetes mellitus. J. Clin. Endocrinol. Metab. 77, 1500-1505. doi: 10.1210/jc.77.6.1500
94. Harley, H. G., Rundle, S. A., Macmillan, J. C., Myring, J., Brook, J. D., Crow, S., et al. (1993). Size of the unstable CTG repeat sequence in relation to pheno-type and parental transmission in myotonic dystrophy. Am. J. Hum. Genet. 52, 1164-1174.
95. Herukka, S. K., Hallikainen, M., Soininen, H., and Pirttila, T. (2005). CSF Abeta42 and tau or phosphorylated tau and prediction of progressive mild cognitive impairment. Neurology 64, 1294-1297. doi: 10.1212/01.WNL.0000156914.16988.56
96. Ho, T. H., Charlet, B. N., Poulos, M. G., Singh, G., Swanson, M. S., and Cooper, T. A. (2004). Muscleblind proteins regulate alternative splicing. EMBO J. 23, 3103-3112. doi: 10.1038/sj.emboj.7600300
97. Holmes, S. E., O'Hearn, E., Rosenblatt, A., Callahan, C., Hwang, H. S., Ingersoll-Ashworth, R. G., et al. (2001). A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2. Nat. Genet. 29, 377-378. doi: 10.1038/ng760
98. Huang, Y., and Mucke, L. (2012). Alzheimer mechanisms and therapeutic strategies. Cell 148, 1204-1222. doi: 10.1016/j.cell.2012.02.040
99. Huang, Z., Bodkin, N. L., Ortmeyer, H. K., Hansen, B. C., and Shuldiner, A. R. (1994). Hyperinsulinemia is associated with altered insulin receptor mRNA splicing in muscle of the spontaneously obese diabetic rhesus monkey. J. Clin. Invest. 94, 1289-1296. doi: 10.1172/JCI117447
100. Huang, Z., Bodkin, N. L., Ortmeyer, H. K., Zenilman, M. E., Webster, N. J., Hansen, B. C., et al. (1996). Altered insulin receptor messenger ribonucleic acid splicing in liver is associated with deterioration of glucose tolerance in the spontaneously obese and diabetic rhesus monkey: analysis of controversy between monkey and human studies. J. Clin. Endocrinol. Metab. 81, 1552-1556. doi: 10.1210/jc.81.4.1552
101. Huguet, A., Medja, F., Nicole, A., Vignaud, A., Guiraud-Dogan, C., Ferry, A., et al. (2012). Molecular, physiological, and motor performance defects in DMSXL mice carrying >1,000 CTG repeats from the human DM1 locus. PLoS Genet. 8:e1003043. doi: 10.1371/journal.pgen.1003043
102. Hund, E., Jansen, O., Koch, M. C., Ricker, K., Fogel, W., Niedermaier, N., et al. (1997). Proximal myotonic myopathy with MRI white matter abnormalities of the brain. Neurology 48, 33-37. doi: 10.1212/WNL.48.1.33
103. Ikeda, Y., Ohta, Y., Kobayashi, H., Okamoto, M., Takamatsu, K., Ota, T., et al. (2012). Clinical features of SCA36: a novel spinocerebellar ataxia with motor neuron involvement (Asidan). Neurology 79, 333-341. doi: 10.1212/WNL.0b013e318260436f
104. Ingelsson, M., Ramasamy, K., Cantuti-Castelvetri, I., Skoglund, L., Matsui, T., Orne, J., et al. (2006). No alteration in tau exon 10 alternative splicing in tangle-bearing neurons of the Alzheimer's disease brain. Acta Neuropathol. 112, 439-449. doi: 10.1007/s00401-006-0095-3
105. Itoh, K., Mitani, M., Kawamoto, K., Futamura, N., Funakawa, I., Jinnai, K., et al. (2010). Neuropathology does not Correlate with Regional Differences in the Extent of Expansion of CTG Repeats in the Brain with Myotonic Dystrophy Ty p e 1. Acta Histochem. Cytochem. 43, 149-156. doi: 10.1267/ahc.10019
106. Iwahashi, C. K., Yasui, D. H., An, H. J., Greco, C. M., Tassone, F., Nannen, K., et al. (2006). Protein composition of the intranuclear inclusions of FXTAS. Brain 129, 256-271. doi: 10.1093/brain/awh650
107. Jaekel, B., Muhlberg, K., Garcia de Arriba, S., Reichenbach, A., Verdaguer, E., Pallas, M., et al. (2006). Neuroprotection associated with alternative splicing of NMDA receptors in rat cortical neurons. Br. J. Pharmacol. 147, 622-633. doi: 10.1038/sj.bjp.0706471
108. James, B. D., Bennett, D. A., Boyle, P. A., Leurgans, S., and Schneider, J. A. (2012). Dementia from Alzheimer disease and mixed pathologies in the oldest old. JAMA 307, 1798-1800. doi: 10.1001/jama.2012.3556
109. Jeganathan, S., von Bergen, M., Mandelkow, E. M., and Mandelkow, E. (2008). The natively unfolded character of tau and its aggregation to Alzheimer-like paired helical filaments. Biochemistry 47, 10526-10539. doi: 10.1021/bi800783d
110. Jiang, H., Mankodi, A., Swanson, M. S., Moxley, R. T., and Thornton, C. A. (2004). Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Hum. Mol. Genet. 13, 3079-3088. doi: 10.1093/hmg/ddh327
111. Jog, S. P., Paul, S., Dansithong, W., Tring, S., Comai, L., and Reddy, S. (2012). RNA Splicing Is Responsive to MBNL1 Dose. PLoS ONE 7:e48825. doi: 10.1371/jour-nal.pone.0048825
112. Johnson, S. A., Rogers, J., and Finch, C. E. (1989). APP-695 transcript prevalence is selectively reduced during Alzheimer's disease in cortex and hippocampus but not in cerebellum. Neurobiol. Aging 10, 755-760. doi: 10.1016/0197-4580(89)90017-1
113. Jolivalt, C. G., Hurford, R., Lee, C. A., Dumaop, W., Rockenstein, E., and Masliah, E. (2010). Type 1 diabetes exaggerates features of Alzheimer's disease in APP transgenic mice. Exp. Neurol. 223, 422-431. doi: 10.1016/j.expneurol.2009. 11.005
114. Jung, H. J., Park, S. S., Mok, J. O., Lee, T. K., Park, C. S., and Park, S. A. (2011). Increased expression of three-repeat isoforms of tau contributes to tau pathology in a rat model of chronic type 2 diabetes. Exp. Neurol. 228, 232-241. doi: 10.1016/j.expneurol.2011.01.012
115. Kabashi, E., Valdmanis, P. N., Dion, P., Spiegelman, D., McConkey, B. J., Vande Velde, C., et al. (2008). TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572-574. doi: 10.1038/ng.132
116. Kalsotra, A., Xiao, X., Ward, A. J., Castle, J. C., Johnson, J. M., Burge, C. B., et al. (2008). A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart. Proc. Natl. Acad. Sci. U.S.A. 105, 20333-20338. doi: 10.1073/pnas.0809045105
117. Kaminsky, P., Poussel, M., Pruna, L., Deibener, J., Chenuel, B., and Brembilla-Perrot, B. (2011). Organ dysfunction and muscular disability in myotonic dystrophy type 1. Medicine (Baltimore) 90, 262-268. doi: 10.1097/MD.0b013e318226046b
118. Kanaan, N. M., Morfini, G. A., LaPointe, N. E., Pigino, G. F., Patterson, K. R., Song, Y., et al. (2011). Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phos-photransferases. J. Neurosci. 31, 9858-9868. doi: 10.1523/JNEUROSCI.0560-11.2011
119. Kanaan, N. M., Morfini, G., Pigino, G., LaPointe, N. E., Andreadis, A., Song, Y., et al. (2012). Phosphorylation in the amino terminus of tau prevents inhibition of anterograde axonal transport. Neurobiol. Aging 33, 826.e15-826.e30. doi: 10.1016/j.neurobiolaging.2011.06.006
120. Kanadia, R. N., Johnstone, K. A., Mankodi, A., Lungu, C., Thornton, C. A., Esson, D., et al. (2003). A muscleblind knockout model for myotonic dystrophy. Science 302, 1978-1980. doi: 10.1126/science.1088583
121. Kanai, Y., Chen, J., and Hirokawa, N. (1992). Microtubule bundling by tau proteins in vivo: analysis of functional domains. EMBO J. 11, 3953-3961.
122. Kassubek, J., Juengling, F. D., Hoffmann, S., Rosenbohm, A., Kurt, A., Jurkat-Rott, K., et al. (2003). Quantification of brain atrophy in patients with myotonic dystrophy and proximal myotonic myopathy: a controlled 3-dimensional magnetic resonance imaging study. Neurosci. Lett. 348, 73-76. doi: 10.1016/S0304-3940(03)00740-7
123. Kawahara, Y., and Mieda-Sato, A. (2012). TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes. Proc. Natl. Acad. Sci. U.S.A. 109, 3347-3352. doi: 10.1073/pnas.1112427109
124. Ke, Y., Dramiga, J., Schutz, U., Kril, J. J., Ittner, L. M., Schroder, H., et al. (2012). Tau-mediated nuclear depletion and cytoplasmic accumulation of SFPQ in Alzheimer's and Pick's disease. PLoS ONE 7:e35678. doi: 10.1371/jour-nal.pone.0035678
125. Kellerer, M., Sesti, G., Seffer, E., Obermaier-Kusser, B., Pongratz, D. E., Mosthaf, L., et al. (1993). Altered pattern of insulin receptor isotypes in skeletal muscle membranes of type 2 (non-insulin-dependent) diabetic subjects. Diabetologia 36, 628-632. doi: 10.1007/BF00404072
126. Kim, D. H., Langlois, M. A., Lee, K. B., Riggs, A. D., Puymirat, J., and Rossi, J. J. (2005). HnRNP H inhibits nuclear export of mRNA containing expanded CUG repeats and a distal branch point sequence. Nucleic Acids Res. 33, 3866-3874. doi: 10.1093/nar/gki698
127. Kim, W., Lee, S., and Hall, G. F. (2010). Secretion of human tau fragments resembling CSF-tau in Alzheimer's disease is modulated by the presence of the exon 2 insert. FEBS Lett. 584, 3085-3088. doi: 10.1016/j.febslet.2010.05.042
128. King, A., Al-Sarraj, S., Troakes, C., Smith, B. N., Maekawa, S., Iovino, M., et al. (2013). Mixed tau, TDP-43 and p62 pathology in FTLD associated with a C9ORF72 repeat expansion and p.Ala239Thr MAPT (tau) variant. Acta Neuropathol. 125, 303-310. doi: 10.1007/s00401-012-1050-0
129. Kino, Y., Washizu, C., Oma, Y., Onishi, H., Nezu, Y., Sasagawa, N., et al. (2009). MBNL and CELF proteins regulate alternative splicing of the skeletal muscle chloride channel CLCN1. Nucleic Acids Res. 37, 6477-6490. doi: 10.1093/nar/gkp681
130. Kiuchi, A., Otsuka, N., Namba, Y., Nakano, I., and Tomonaga, M. (1991). Presenile appearance of abundant Alzheimer's neurofibrillary tangles without senile plaques in the brain in myotonic dystrophy. Acta Neuropathol. 82, 1-5. doi: 10.1007/BF00310916
131. Klein, A. F., Gasnier, E., and Furling, D. (2011). Gain of RNA function in pathological cases: Focus on myotonic dystrophy. Biochimie 93, 2006-2012. doi: 10.1016/j.biochi.2011.06.028
132. Kornblum, C., Reul, J., Kress, W., Grothe, C., Amanatidis, N., Klockgether, T., et al. (2004). Cranial magnetic resonance imaging in genetically proven myotonic dystrophy type 1 and 2. J. Neurol. 251, 710-714. doi: 10.1007/s00415-004-0408-1
133. Kuru, S., Sakai, M., Yoshida, M., Mimuro, M., and Hashizume, Y. (2013). Neurofibrillary tangles in the peripheral sympathetic ganglia of patients with myotonic dystrophy. Neuropathol. Appl. Neurobiol. 39, 585-588. doi: 10.1111/nan.12043
134. Kuyumcu-Martinez, N. M., and Cooper, T. A. (2006). Misregulation of alternative splicing causes pathogenesis in myotonic dystrophy. Prog. Mol. Subcell. Biol. 44, 133-159. doi: 10.1007/978-3-540-34449-0_7
135. Kuyumcu-Martinez, N. M., Wang, G. S., and Cooper, T. A. (2007). Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation. Mol. Cell 28, 68-78. doi: 10.1016/j.molcel.2007.07.027
136. Laberge, L., Gagnon, C., and Dauvilliers, Y. (2013). Daytime sleepiness and myotonic dystrophy. Curr. Neurol. Neurosci. Rep. 13, 340. doi: 10.1007/s11910-013-0340-9
137. Ladd, A. N., Charlet, N., and Cooper, T. A. (2001). The CELF family of RNA binding proteins is implicated in cell-specific and developmentally regulated alternative splicing. Mol. Cell. Biol. 21, 1285-1296. doi: 10.1128/MCB.21.4.1285-1296.2001
138. Ladd, A. N., Nguyen, N. H., Malhotra, K., and Cooper, T. A. (2004). CELF6, a member of the CELF family of RNA-binding proteins, regulates muscle-specific splicing enhancer-dependent alternative splicing. J. Biol. Chem. 279, 17756-17764. doi: 10.1074/jbc.M310687200
139. Lagier-Tourenne, C., Polymenidou, M., Hutt, K. R., Vu, A. Q., Baughn, M., Huelga, S. C., et al. (2012). Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat. Neurosci. 15, 1488-1497. doi: 10.1038/nn.3230
140. Lambert, J. C., Zelenika, D., Hiltunen, M., Chouraki, V., Combarros, O., Bullido, M. J., et al. (2011). Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations. Neurobiol. Aging 32, 756.e11-756.e55. doi: 10.1016/j.neurobiolaging.2010.11.022
141. LaPointe, N. E., Morfini, G., Pigino, G., Gaisina, I. N., Kozikowski, A. P., Binder, L. I., et al. (2009). The amino terminus of tau inhibits kinesin-dependent axonal transport: implications for filament toxicity. J. Neurosci. Res. 87, 440-451. doi: 10.1002/jnr.21850
142. Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Sengupta, U., Guerrero-Munoz, M. J., Kiritoshi, T., Neugebauer, V., et al. (2012). Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau. Sci. Rep. 2, 700. doi: 10.1038/srep00700
143. La Spada, A. R., and Taylor, J. P. (2010). Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat. Rev. Genet. 11, 247-258. doi: 10.1038/nrg2748
144. Laurie, D. J., and Seeburg, P. H. (1994). Regional and developmental heterogeneity in splicing of the rat brain NMDAR1 mRNA. J. Neurosci. 14, 3180-3194.
145. Leboucher, A., Laurent, C., Fernandez-Gomez, F. J., Burnouf, S., Troquier, L., Eddarkaoui, S., et al. (2013). Detrimental effects of diet-induced obesity on tau pathology are independent of insulin resistance in tau transgenic mice. Diabetes 62, 1681-1688. doi: 10.2337/db12-0866
146. Lee, J. E., and Cooper, T. A. (2009). Pathogenic mechanisms of myotonic dystrophy. Biochem. Soc. Trans. 37, 1281-1286. doi: 10.1042/BST0371281
147. Lefebvre, S., Burglen, L., Reboullet, S., Clermont, O., Burlet, P., Viollet, L., et al. (1995). Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80, 155-165. doi: 10.1016/0092-8674(95)90460-3
148. Leprince, C., Romero, F., Cussac, D., Vayssiere, B., Berger, R., Tavitian, A., et al. (1997). A new member of the amphiphysin family connecting endocyto-sis and signal transduction pathways. J. Biol. Chem. 272, 15101-15105. doi: 10.1074/jbc.272.24.15101
149. Leroy, O., Dhaenens, C. M., Schraen-Maschke, S., Belarbi, K., Delacourte, A., Andreadis, A., et al. (2006a). ETR-3 represses Tau exons 2/3 inclusion, a splicing event abnormally enhanced in myotonic dystrophy type I. J. Neurosci. Res. 84, 852-859. doi: 10.1002/jnr.20980
150. Leroy, O., Wang, J., Maurage, C. A., Parent, M., Cooper, T., Buee, L., et al. (2006b). Brain-specific change in alternative splicing of Tau exon 6 in myotonic dystrophy type 1. Biochim. Biophys. Acta 1762, 460-467. doi: 10.1016/j.bbadis.2005.12.003
151. Li, W., and Lee, V. M. (2006). Characterization of two VQIXXK motifs for tau fibrillization in vitro. Biochemistry 45, 15692-15701. doi: 10.1021/bi061422+
152. Li, Z. G., Zhang, W., and Sima, A. A. (2007). Alzheimer-like changes in rat models of spontaneous diabetes. Diabetes 56, 1817-1824. doi: 10.2337/db07-0171
153. Lin, X., Miller, J. W., Mankodi, A., Kanadia, R. N., Yuan, Y., Moxley, R. T., et al. (2006). Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy. Hum. Mol. Genet. 15, 2087-2097. doi: 10.1093/hmg/ddl132
154. Ling, S. C., Albuquerque, C. P., Han, J. S., Lagier-Tourenne, C., Tokunaga, S., Zhou, H., et al. (2010). ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS. Proc. Natl. Acad. Sci. U.S.A. 107, 13318-13323. doi: 10.1073/pnas.1008227107
155. Liquori, C. L., Ricker, K., Moseley, M. L., Jacobsen, J. F., Kress, W., Naylor, S. L., et al. (2001). Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293, 864-867. doi: 10.1126/science.1062125
156. Logue, M. W., Schu, M., Vardarajan, B. N., Buros, J., Green, R. C., Go, R. C., et al. (2011). A comprehensive genetic association study of Alzheimer disease in African Americans. Arch. Neurol 68, 1569-1579. doi: 10.1001/archneu-rol.2011.646
157. Lotti, R, Imlach, W. L., Saieva, L., Beck, E. S., Hao le, T, Li, D. K., et al. (2012). An SMN-dependent U12 splicing event essential for motor circuit function. Cell 151, 440-454. doi: 10.1016/j.cell.2012.09.012
158. Luo, M. H., Leski, M. L., and Andreadis, A. (2004a). Tauisoforms which contain the domain encoded by exon 6 and their role in neurite elongation. /. Cell Biochem. 91, 880-895. doi: 10.1002/jcb.20029
159. Luo, M. H., Tse, S. W., Memmott, J., and Andreadis, A. (2004b). Novel isoforms of tau that lack the microtubule-binding domain. /. Neurochem. 90, 340-351. doi: 10.1111/j.1471-4159.2004.02508.x
160. Machuca-Tzili, L., Brook, D., and Hilton-Jones, D. (2005). Clinical and molecular aspects of the myotonic dystrophies: a review. Muscle Nerve 32, 1-18. doi: 10.1002/mus.20301
161. ; untranslated region of the gene. Science 255, 1253-1255. doi: 10.1126/sci-ence.1546325
162. Malloy, P., Mishra, S. K., and Adler, S. H. (1990). Neuropsychological deficits in myotonic muscular dystrophy. /. Neurol Neurosurg. Psychiatr. 53, 1011-1013. doi: 10.1136/jnnp.53.11.1011
163. Mandelkow, E. M., and Mandelkow, E. (2012). Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb. Perspect Med. 2, a006247. doi: 10.1101/cshperspect.a006247
164. Mandelkow, E. M., Thies, E., Trinczek,., Biernat, J., and Mandelkow, E. (2004). MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons./. CellBiol. 167, 99-110. doi: 10.1083/jcb.200401085
165. Marteyn, A., Maury, Y., Gauthier, M. M., Lecuyer, C., Vernet, R., Denis, J. A., et al. (2011). Mutant human embryonic stem cells reveal neurite and synapse formation defects in type 1 myotonic dystrophy. Cell Stem Cell 8, 434-444. doi: 10.1016/j.stem.2011.02.004
166. Martin, C. L., Duvall, J. A., Ilkin, Y., Simon, J. S., Arreaza, M. G., Wilkes, K., et al. (2007). Cytogenetic and molecular characterization of A2BP1/FOX1 as a candidate gene for autism. Am. J. Med. Genet. Neuropsychiatr. Genet. 144B, 869-876. doi: 10.1002/ajmg.b.30530
167. Martorell, L., Monckton, D. G., Gamez, J., Johnson, K. J., Gich, I., Lopez De Munain, A., et al. (1998). Progression of somatic CTG repeat length heterogeneity in the blood cells of myotonic dystrophy patients. Hum. Mol Genet. 7, 307-312. doi: 10.1093/hmg/7.2.307
168. Mastroyiannopoulos, N. P., Shammas, C, and Phylactou, L. A. (2010). Tackling the pathogenesis of RNA nuclear retention in myotonic dystrophy. Biol Cell 102, 515-523. doi: 10.1042/BC20100040
169. Maurage, S A., Udd, B., Ruchoux, M. M., Vermersch, P., Kalimo, H., Krahe, R., et al. (2005). Similar brain tau pathology in DM2/PROMM and DMl/Steinert disease. Neurology 65, 1636-1638. doi: 10.1212/01.wnl.0000184585.93864.4e
170. McVicker, D. P., Chrin, L. R., and Berger, C. L. (2011). The nucleotide-binding state of microtubules modulates kinesin processivity and the ability of Tau to inhibit kinesin-mediated transport. /. Biol. Chem. 286, 42873-42880. doi: 10.1074/jbc.Ml 11.292987
171. Meola, G., Sansone, V., Perani, D., Colleluori, A., Cappa, S., Cotelli, M., et al. (1999). Reduced cerebral blood flow and impaired visual-spatial function in proximal myotonic myopathy. Neurology 53, 1042-1050. doi: 10.1212/WNL.53.5.1042
172. Meola, G., Sansone, V., Perani, D., Scarone, S., Cappa, S., Dragoni, C, et al. (2003). Executive dysfunction and avoidant personality trait in myotonic dystrophy type 1 (DM-1) and in proximal myotonic myopathy (PROMM/DM-2). Neuromuscul Disord. 13, 813-821. doi: 10.1016/S0960-8966(03)00137-8
173. Miller, J. W., Urbinati, C. R., Teng-Umnuay, P., Stenberg, M. G., Byrne, B. J., Thornton, S{cyrillic} A., et al. (2000). Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J. 19, 4439-4448. doi: 10.1093/emboj/19.17.4439
174. Mills, J. D., and Janitz, M. (2012). Alternative splicing of mRNA in the molecular pathology of neurodegenerative diseases. Neurobiol. Aging 33, 1012.ell-1012.e24. doi: 10.1016/j.neurobiolaging.2011.10.030
175. Minnerop, M., Luders, E., Specht, K., Ruhlmann, J., Schneider-Gold, C, Schroder, R., et al. (2008). Grey and white matter loss along cerebral midline structures in myotonic dystrophy type 2. /. Neurol. 255, 1904-1909. doi: 10.1007/s00415-008-0997-1
176. Minnerop, M., Weber, B., Schoene-Bake, J. C., Roeske, S., Mirbach, S., Anspach, C., et al. (2011). The brain in myotonic dystrophy 1 and 2: evidence for a predominant white matter disease. Brain 134, 3530-3546. doi: 10.1093/brain/awr299
177. Morgan, K. (2011). The three new pathways leading to Alzheimer's disease. Neuropathol. Appl. Neurobiol. 37, 353-357. doi: 10.1111/j.1365-2990.2011.01181.x
178. Moseley, M. L., Zu, T., Ikeda, Y., Gao, W., Mosemiller, A. K., Daughters, R. S., et al. (2006). Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nat. Genet. 38, 758-769. doi: 10.1038/ng1827
179. Mosthaf, L., Vogt, B., Haring, H. U., and Ullrich, A. (1991). Altered expression of insulin receptor types A and B in the skeletal muscle of non-insulin-dependent diabetes mellitus patients. Proc. Natl. Acad. Sci. U.S.A. 88, 4728-4730. doi: 10.1073/pnas.88.11.4728
180. Moxley, R. T., Corbett, A. J., Minaker, K. L., and Rowe, J. W. (1984). Whole body insulin resistance in myotonic dystrophy. Ann. Neurol. 15, 157-162. doi: 10.1002/ana.410150208
181. Mukrasch, M. D., Bibow, S., Korukottu, J., Jeganathan, S., Biernat, J., Griesinger, C., et al. (2009). Structural polymorphism of 441-residue tau at single residue resolution. PLoS Biol. 7:e34. doi: 10.1371/journal.pbio.1000034
182. Mulot, S. F., Hughes, K., Woodgett, J. R., Anderton, B. H., and Hanger, D. P. (1994). PHF-tau from Alzheimer's brain comprises four species on SDS-PAGE which can be mimicked by in vitro phosphorylation of human brain tau by glycogen synthase kinase-3 beta. FEBS Lett. 349, 359-364. doi: 10.1016/0014-5793(94)00702-0
183. Naka, H., Imon, Y., Ohshita, T., Honjo, K., Kitamura, T., Mimori, Y., et al. (2002). Magnetization transfer measurements of cerebral white matter in patients with myotonic dystrophy. J. Neurol. Sci. 193, 111-116. doi: 10.1016/S0022-510X(01)00652-9
184. Nakamori, M., Sobczak, K., Puwanant, A., Welle, S., Eichinger, K., Pandya, S., et al. (2013). Splicing biomarkers of disease severity in myotonic dystrophy. Ann. Neurol. doi: 10.1002/ana.23992. [Epub ahead of print].
185. Nakamori, M., Takahashi, T., Yamazaki, Y., Kurashige, T., Yamawaki, T., and Matsumoto, M. (2012). Cyclin-dependent kinase 5 immunoreac-tivity for granulovacuolar degeneration. Neuroreport 23, 867-872. doi: 10.1097/WNR.0b013e328358720b
186. Nakaya, T., Alexiou, P., Maragkakis, M., Chang, A., and Mourelatos, Z. (2013). FUS regulates genes coding for RNA-binding proteins in neurons by binding to their highly conserved introns. RNA 19, 498-509. doi: 10.1261/rna.0378 04.112
187. Noguchi, M., Yoshita, M., Matsumoto, Y., Ono, K., Iwasa, K., and Yamada, M. (2005). Decreased beta-amyloid peptide42 in cerebrospinal fluid of patients with progressive supranuclear palsy and corticobasal degeneration. J. Neurol. Sci. 237, 61-65. doi: 10.1016/j.jns.2005.05.015
188. Norgren, S., Zierath, J., Galuska, D., Wallberg-Henriksson, H., and Luthman, H. (1993). Differences in the ratio of RNA encoding two isoforms of the insulin receptor between control and NIDDM patients. The RNA variant without Exon 11 predominates in both groups. Diabetes 42, 675-681. doi: 10.2337/diab.42.5.675
189. Norgren, S., Zierath, J., Wedell, A., Wallberg-Henriksson, H., and Luthman, H. (1994). Regulation of human insulin receptor RNA splicing in vivo. Proc. Natl. Acad. Sci. U.S.A. 91, 1465-1469. doi: 10.1073/pnas.91.4.1465
190. Novelli, G., Gennarelli, M., Zelano, G., Pizzuti, A., Fattorini, C., Caskey, C. T., et al. (1993). Failure in detecting mRNA transcripts from the mutated allele in myotonic dystrophy muscle. Biochem. Mol. Biol. Int. 29, 291-297.
191. Okamoto, K., Hirai, S., Iizuka, T., Yanagisawa, T., and Watanabe, M. (1991). Reexamination of granulovacuolar degeneration. Acta Neuropathol. 82, 340-345. doi: 10.1007/BF00296544
192. Ono, S., Kurisaki, H., Sakuma, A., and Nagao, K. (1995). Myotonic dystrophy with alveolar hypoventilation and hypersomnia: a clinicopathological study. J. Neurol. Sci. 128, 225-231. doi: 10.1016/0022-510X(94)00244-I
193. Orozco, D., Tahirovic, S., Rentzsch, K., Schwenk, B. M., Haass, C., and Edbauer, D. (2012). Loss of fused in sarcoma (FUS) promotes pathological Tau splicing. EMBO Rep. 13, 759-764. doi: 10.1038/embor.2012.90
194. Ota, M., Sato, N., Ohya, Y., Aoki, Y., Mizukami, K., Mori, T., et al. (2006). Relationship between diffusion tensor imaging and brain morphology in patients with myotonic dystrophy. Neurosci. Lett. 407, 234-239. doi: 10.1016/j.neulet.2006.08.077
195. Otten, A. D., and Tapscott, S. J. (1995). Triplet repeat expansion in myotonic dystrophy alters the adjacent chromatin structure. Proc. Natl. Acad. Sci. U.S.A. 92, 5465-5469. doi: 10.1073/pnas.92.12.5465
196. Otto, M., Esselmann, H., Schulz-Shaeffer, W., Neumann, M., Schroter, A., Ratzka, P., et al. (2000). Decreased beta-amyloid1-42 in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurology 54, 1099-1102. doi: 10.1212/WNL.54.5.1099
197. Oyamada, R., Hayashi, M., Katoh, Y., Tsuchiya, K., Mizutani, T., Tominaga, I., et al. (2006). Neurofibrillary tangles and deposition of oxidative products in the brain in cases of myotonic dystrophy. Neuropathology 26, 107-114. doi: 10.1111/j.1440-1789.2006.00662.x
198. Papon, M. A., El Khoury, N. B., Marcouiller, F., Julien, C., Morin, F., Bretteville, A., et al. (2013). Deregulation of protein phosphatase 2A and hyperphospho-rylation of tau protein following onset of diabetes in NOD mice. Diabetes 62, 609-617. doi: 10.2337/db12-0187
199. Paul, S., Dansithong, W., Jog, S. P., Holt, I., Mittal, S., Brook, J. D., et al. (2011). Expanded CUG repeats Dysregulate RNA splicing by altering the stoichiom-etry of the muscleblind 1 complex. J. Biol. Chem. 286, 38427-38438. doi: 10.1074/jbc.M111.255224
200. Pellizzoni, L., Yong, J., and Dreyfuss, G. (2002). Essential role for the SMN complex in the specificity of snRNP assembly. Science 298, 1775-1779. doi: 10.1126/science.1074962
201. Peric, S., Mandic-Stojmenovic, G., Markovic, I., Stefanova, E., Ilic, V., Parojcic, A., et al. (2013a). Cerebrospinal fluid biomarkers of neurodegeneration in patients with juvenile and classic myotonic dystrophy type 1. Eur. J. Neurol. doi: 10.1111/ene.12237. [Epub ahead of print].
202. Peric, S., Stojanovic, V. R., Nikolic, A., Kacar, A., Basta, I., Pavlovic, S., et al. (2013b). Peripheral neuropathy in patients with myotonic dystrophy type 1. Neurol. Res. 35, 331-335. doi: 10.1179/1743132812Y.0000000144
203. Perseghin, G., Comola, M., Scifo, P., Benedini, S., De Cobelli, F., Lanzi, R., et al. (2004). Postabsorptive and insulin-stimulated energy and protein metabolism in patients with myotonic dystrophy type 1. Am. J. Clin. Nutr. 80, 357-364.
204. Philips, A. V., Timchenko, L. T., and Cooper, T. A. (1998). Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science 280, 737-741. doi: 10.1126/science.280.5364.737
205. Piazzon, N., Rage, F., Schlotter, F., Moine, H., Branlant, C., and Massenet, S. (2008). In vitro and in cellulo evidences for association of the survival of motor neuron complex with the fragile X mental retardation protein. J. Biol. Chem. 283, 5598-5610. doi: 10.1074/jbc.M707304200
206. Planel, E., Tatebayashi, Y., Miyasaka, T., Liu, L., Wang, L., Herman, M., et al. (2007). Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J. Neurosci. 27, 13635-13648. doi: 10.1523/JNEUROSCI.3949-07.2007
207. Polymenidou, M., Lagier-Tourenne, C., Hutt, K. R., Huelga, S. C., Moran, J., Liang, T. Y., et al. (2011). Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat. Neurosci. 14, 459-468. doi: 10.1038/nn.2779
208. Querido, E., Gallardo, F., Beaudoin, M., Menard, C., and Chartrand, P. (2011). Stochastic and reversible aggregation of mRNA with expanded CUG-triplet repeats. J. Cell Sci. 124, 1703-1714. doi: 10.1242/jcs.073270
209. Rademakers, R., Melquist, S., Cruts, M., Theuns, J., Del-Favero, J., Poorkaj, P., et al. (2005). High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum. Mol. Genet. 14, 3281-3292. doi: 10.1093/hmg/ddi361
210. Rakocevic Stojanovic, V., Peric, S., Lavrnic, D., Popovic, S., Ille, T., Stevic, Z., et al. (2010). Leptin and the metabolic syndrome in patients with myotonic dystrophy type 1. Acta Neurol. Scand. 121, 94-98. doi: 10.1111/j.1600-0404.2009. 01237.x
211. Ranum, L. P., and Cooper, T. A. (2006). RNA-mediated neuromuscular disorders. Annu. Rev. Neurosci. 29, 259-277. doi: 10.1146/annurev.neuro.29.051605. 113014
212. Reger, M. A., Watson, G. S., Green, P. S., Baker, L. D., Cholerton, B., Fishel, M. A., et al. (2008). Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J. Alzheimers. Dis. 13, 323-331.
213. Renoux, A. J., and Todd, P. K. (2012). Neurodegeneration the RNA way. Prog. Neurobiol. 97, 173-189. doi: 10.1016/j.pneurobio.2011.10.006
214. Renton, A. E., Majounie, E., Waite, A., Simon-Sanchez, J., Rollinson, S., Gibbs, J. R., et al. (2011). A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257-268. doi: 10.1016/j.neuron.2011.09.010
215. Rodriguez, J. J., Olabarria, M., Chvatal, A., and Verkhratsky, A. (2009). Astroglia in dementia and Alzheimer's disease. Cell Death Differ. 16, 378-385. doi: 10.1038/cdd.2008.172
216. Rogelj, B., Easton, L. E., Bogu, G. K., Stanton, L. W., Rot, G., Curk, T., et al. (2012). Widespread binding of FUS along nascent RNA regulates alternative splicing in the brain. Sci. Rep. 2, 603. doi: 10.1038/srep00603
217. Romeo, V. (2012). Myotonic Dystrophy Type 1 or Steinert's disease. Adv. Exp. Med. Biol. 724, 239-257. doi: 10.1007/978-1-4614-0653-2_18
218. Romeo, V., Pegoraro, E., Ferrati, C., Squarzanti, F., Soraru, G., Palmieri, A., et al. (2010). Brain involvement in myotonic dystrophies: neuroimaging and neuropsychological comparative study in DM1 and DM2. J. Neurol. 257, 1246-1255. doi: 10.1007/s00415-010-5498-3
219. Rosenblum, W. I., and Ghatak, N. R. (1979). Lewy bodies in the presence of Alzheimer's disease. Arch. Neurol. 36, 170-171. doi: 10.1001/arch-neur.1979.00500390088011
220. Rubinsztein, J. S., Rubinsztein, D. C., Goodburn, S., and Holland, A. J. (1998). Apathy and hypersomnia are common features of myotonic dystrophy. J. Neurol. Neurosurg. Psychiatr. 64, 510-515. doi: 10.1136/jnnp.64.4.510
221. Rubinsztein, J. S., Rubinsztein, D. C., McKenna, P. J., Goodburn, S., and Holland, A. J. (1997). Mild myotonic dystrophy is associated with memory impairment in the context of normal general intelligence. J. Med. Genet. 34, 229-233. doi: 10.1136/jmg.34.3.229
222. Rudnicki, D. D., Holmes, S. E., Lin, M. W., Thornton, C. A., Ross, C. A., and Margolis, R. L. (2007). Huntington's disease-like 2 is associated with CUG repeat-containing RNA foci. Ann. Neurol. 61, 272-282. doi: 10.1002/ana.21081
223. Rumbaugh, G., Prybylowski, K., Wang, J. F., and Vicini, S. (2000). Exon 5 and spermine regulate deactivation of NMDA receptor subtypes. J. Neurophysiol. 83, 1300-1306.
224. Sahara, N., Maeda, S., Yoshiike, Y., Mizoroki, T., Yamashita, S., Murayama, M., et al. (2007). Molecular chaperone-mediated tau protein metabolism counteracts the formation of granular tau oligomers in human brain. J. Neurosci. Res. 85, 3098-3108. doi: 10.1002/jnr.21417
225. Sato-Harada, R., Okabe, S., Umeyama, T., Kanai, Y., and Hirokawa, N. (1996). Microtubule-associated proteins regulate microtubule function as the track for intracellular membrane organelle transports. Cell Struct. Funct. 21, 283-295. doi: 10.1247/csf.21.283
226. Savkur, R. S., Philips, A. V., and Cooper, T. A. (2001). Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat. Genet. 29, 40-47. doi: 10.1038/ng704
227. Savkur, R. S., Philips, A. V., Cooper, T. A., Dalton, J. C., Moseley, M. L., Ranum, L. P., et al. (2004). Insulin receptor splicing alteration in myotonic dystrophy type 2. Am. J. Hum. Genet. 74, 1309-1313. doi: 10.1086/421528
228. Schara, U., and Schoser, B. G. (2006). Myotonic dystrophies type 1 and 2: a summary on current aspects. Semin. Pediatr. Neurol. 13, 71-79. doi: 10.1016/j.spen.2006.06.002
229. Schmitt, H. P. (2005). On the paradox of ion channel blockade and its benefits in the treatment of Alzheimer disease. Med. Hypotheses 65, 259-265. doi: 10.1016/j.mehy.2005.03.011
230. Schoser, B., and Timchenko, L. (2010). Myotonic dystrophies 1 and 2: complex diseases with complex mechanisms. Curr. Genomics 11, 77-90. doi: 10.2174/138920210790886844
231. Schraen-Maschke, S., Sergeant, N., Dhaenens, C. M., Bombois, S., Deramecourt, V., Caillet-Boudin, M. L., et al. (2008). Tau as a biomarker of neurodegenerative diseases. Biomark. Med. 2, 363-384. doi: 10.2217/17520363.2.4.363
232. Schweers, O., Schonbrunn-Hanebeck, E., Marx, A., and Mandelkow, E. (1994). Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structure. J. Biol. Chem. 269, 24290-24297.
233. Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., et al. (2007). Strong association of de novo copy number mutations with autism. Science 316, 445-449. doi: 10.1126/science.1138659
234. Seitz, A., Kojima, H., Oiwa, K., Mandelkow, E. M., Song, Y. H., and Mandelkow, E. (2002). Single-molecule investigation of the interference between kinesin, tau and MAP2c. EMBO J. 21, 4896-4905. doi: 10.1093/emboj/cdf503
235. Sellier, C., Rau, F., Liu, Y., Tassone, F., Hukema, R. K., Gattoni, R., et al. (2010). Sam68 sequestration and partial loss of function are associated with splicing alterations in FXTAS patients. EMBO J. 29, 1248-1261. doi: 10.1038/emboj.2010.21
236. Sergeant, N., Bretteville, A., Hamdane, M., Caillet-Boudin, M. L., Grognet, P., Bombois, S., et al. (2008). Biochemistry of Tau in Alzheimer's disease and related neurological disorders. Expert Rev. Proteomics 5, 207-224. doi: 10.1586/14789450.5.2.207
237. Sergeant, N., Delacourte, A., and Buee, L. (2005). Tau protein as a differential biomarker of tauopathies. Biochim. Biophys. Acta 1739, 179-197. doi: 10.1016/j.bbadis.2004.06.020
238. Sergeant, N., Sablonniere, B., Schraen-Maschke, S., Ghestem, A., Maurage, C. A., Wattez, A., et al. (2001). Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1. Hum. Mol. Genet. 10, 2143-2155. doi: 10.1093/hmg/10.19.2143
239. Seshadri, S., Fitzpatrick, A. L., Ikram, M. A., DeStefano, A. L., Gudnason, V., Boada, M., et al. (2010). Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303, 1832-1840. doi: 10.1001/jama.2010.574
240. Sesti, G., Marini, M. A., Tullio, A. N., Montemurro, A., Borboni, P., Fusco, A., et al. (1991). Altered expression of the two naturally occurring human insulin receptor variants in isolated adipocytes of non-insulin-dependent diabetes mellitus patients. Biochem. Biophys. Res. Commun. 181, 1419-1424. doi: 10.1016/0006-291X(91)92097-4
241. Shahpasand, K., Uemura, I., Saito, T., Asano, T., Hata, K., Shibata, K., et al. (2012). Regulation of mitochondrial transport and inter-microtubule spacing by tau phosphorylation at the sites hyperphosphorylated in Alzheimer's disease. J. Neurosci. 32, 2430-2441. doi: 10.1523/JNEUROSCI.5927-11.2012
242. Shankar, G. M., Bloodgood, B. L., Townsend, M., Walsh, D. M., Selkoe, D. J., and Sabatini, B. L. (2007). Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type gluta-mate receptor-dependent signaling pathway. J. Neurosci. 27, 2866-2875. doi: 10.1523/JNEUROSCI.4970-06.2007
243. Shemesh, E., Rudich, A., Harman-Boehm, I., and Cukierman-Yaffe, T. (2012). Effect of intranasal insulin on cognitive function: a systematic review. J. Clin. Endocrinol. Metab. 97, 366-376. doi: 10.1210/jc.2011-1802
244. Sicot, G., Gourdon, G., and Gomes-Pereira, M. (2011). Myotonic dystrophy, when simple repeats reveal complex pathogenic entities: new findings and future challenges. Hum. Mol. Genet. 20, R116-R123. doi: 10.1093/hmg/ddr343
245. Simon-Sanchez, J., Dopper, E. G., Cohn-Hokke, P. E., Hukema, R. K., Nicolaou, N., Seelaar, H., et al. (2012). The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions. Brain 135, 723-735. doi: 10.1093/brain/awr353
246. Sjogren, M., Davidsson, P., Wallin, A., Granerus, A. K., Grundstrom, E., Askmark, H., et al. (2002). Decreased CSF-beta-amyloid 42 in Alzheimer's disease and amyotrophic lateral sclerosis may reflect mismetabolism of beta-amyloid induced by disparate mechanisms. Dement. Geriatr. Cogn. Disord. 13, 112-118. doi: 10.1159/000048642
247. Smith, P. Y., Delay, C., Girard, J., Papon, M. A., Planel, E., Sergeant, N., et al. (2011). MicroRNA-132 loss is associated with tau exon 10 inclusion in progressive supranuclear palsy. Hum. Mol. Genet. 20, 4016-4024. doi: 10.1093/hmg/ddr330
248. Soreq, L., Bergman, H., Israel, Z., and Soreq, H. (2012). Exon arrays reveal alternative splicing aberrations in Parkinson's disease leukocytes. Neurodegener. Dis. 10, 203-206. doi: 10.1159/000332598
249. Souter, S., and Lee, G. (2010). Tubulin-independent tau in Alzheimer's disease and cancer: implications for disease pathogenesis and treatment. Curr. Alzheimer Res. 7, 697-707. doi: 10.2174/156720510793611637
250. Sreedharan, J., Blair, I. P., Tripathi, V. B., Hu, X., Vance, C., Rogelj, B., et al. (2008). TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668-1672. doi: 10.1126/science.1154584
251. Stoothoff, W., Jones, P. B., Spires-Jones, T. L., Joyner, D., Chhabra, E., Bercury, K., et al. (2009). Differential effect of three-repeat and four-repeat tau on mito-chondrial axonal transport. J. Neurochem. 111, 417-427. doi: 10.1111/j.1471-4159.2009.06316.x
252. Suenaga, K., Lee, K. Y., Nakamori, M., Tatsumi, Y., Takahashi, M. P., Fujimura, H., et al. (2012). Muscleblind-like 1 knockout mice reveal novel splicing defects in the myotonic dystrophy brain. PLoS ONE 7:e33218. doi: 10.1371/jour-nal.pone.0033218
253. Tanaka, S., Shiojiri, S., Takahashi, Y., Kitaguchi, N., Ito, H., Kameyama, M., et al. (1989). Tissue-specific expression of three types of beta-protein precursor mRNA: enhancement of protease inhibitor-harboring types in Alzheimer's disease brain. Biochem. Biophys. Res. Commun. 165, 1406-1414. doi: 10.1016/0006-291X(89)92760-5
254. Taneja, K.L., McCurrach, M., Schalling, M., Housman, D., and Singer, R. H.(1995). Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J. Cell Biol. 128, 995-1002. doi: 10.1083/jcb.128.6.995
255. Thornton, C. A., Wymer, J. P., Simmons, Z., McClain, C., and Moxley, R. T. 3rd. (1997). Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene. Nat. Genet. 16, 407-409. doi: 10.1038/ng0897-407
256. Tollervey, J. R., Curk, T., Rogelj, B., Briese, M., Cereda, M., Kayikci, M., et al. (2011). Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat. Neurosci. 14, 452-458. doi: 10.1038/nn.2778
257. Trabzuni, D., Wray, S., Vandrovcova, J., Ramasamy, A., Walker, R., Smith, C., et al. (2012). MAPT expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies. Hum. Mol. Genet. 21, 4094-4103. doi: 10.1093/hmg/dds238
258. Tran, H., Gourrier, N., Lemercier-Neuillet, C., Dhaenens, C. M., Vautrin, A., Fernandez-Gomez, F. J., et al. (2011). Analysis of exonic regions involved in nuclear localization, splicing activity, and dimerization of Muscleblind-like-1 isoforms. J. Biol. Chem. 286, 16435-16446. doi: 10.1074/jbc.M110.194928
259. Traynelis, S. F., Burgess, M. F., Zheng, F., Lyuboslavsky, P., and Powers, J. L. (1998). Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subunit. J. Neurosci. 18, 6163-6175.
260. Traynelis, S. F., Hartley, M., and Heinemann, S. F. (1995). Control of proton sensitivity of the NMDA receptor by RNA splicing and polyamines. Science 268, 873-876. doi: 10.1126/science.7754371
261. Trinczek, B., Ebneth, A., Mandelkow, E. M., and Mandelkow, E. (1999). Tau regulates the attachment/detachment but not the speed of motors in microtubule-dependent transport of single vesicles and organelles. J. Cell. Sci. 112(Pt 14), 2355-2367.
262. Turner, C., and Hilton-Jones, D. (2010). The myotonic dystrophies: diagnosis and management. J. Neurol. Neurosurg. Psychiatr. 81, 358-367. doi: 10.1136/jnnp.2008.158261
263. Twine, N. A., Janitz, K., Wilkins, M. R., and Janitz, M. (2011). Whole tran-scriptome sequencing reveals gene expression and splicing differences in brain regions affected by Alzheimer's disease. PLoS ONE 6:e16266. doi: 10.1371/jour-nal.pone.0016266
264. Udd, B., and Krahe, R. (2012). The myotonic dystrophies: molecular, clinical, and therapeutic challenges. Lancet Neurol. 11, 891-905. doi: 10.1016/S1474-4422(12)70204-1
265. Umeda, T., Yamashita, T., Kimura, T., Ohnishi, K., Takuma, H., Ozeki, T., et al. (2013). Neurodegenerative disorder FTDP-17-related tau intron 10 +16C-> T mutation increases tau exon 10 splicing and causes tauopathy in transgenic mice. Am. J. Pathol. 183, 211-225. doi: 10.1016/j.ajpath.2013.03.015
266. Uryu, K., Nakashima-Yasuda, H., Forman, M. S., Kwong, L. K., Clark, C. M., Grossman, M., et al. (2008). Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J. Neuropathol. Exp. Neurol. 67, 555-564. doi: 10.1097/NEN.0b013e31817713b5
267. Vance, C., Rogelj, B., Hortobagyi, T., De Vos, K. J., Nishimura, A. L., Sreedharan, J., et al. (2009). Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323, 1208-1211. doi: 10.1126/sci-ence.1165942
268. Van Everbroeck, B., Green, A. J., Pals, P., Martin, J. J., and Cras, P. (1999). Decreased levels of Amyloid-beta 1-42 in cerebrospinal fluid of Creutzfeldt-Jakob disease patients. J. Alzheimers. Dis. 1, 419-424.
269. Vermersch, P., Sergeant, N., Ruchoux, M. M., Hofmann-Radvanyi, H., Wattez, A., Petit, H., et al. (1996). Specific tau variants in the brains of patients with myotonic dystrophy. Neurology 47, 711-717. doi: 10.1212/WNL.47.3.711
270. Vershinin, M., Carter, B. C., Razafsky, D. S., King, S. J., and Gross, S. P. (2007). Multiple-motor based transport and its regulation by Tau. Proc. Natl. Acad. Sci. U.S.A. 104, 87-92. doi: 10.1073/pnas.0607919104
271. Vershinin, M., Xu, J., Razafsky, D. S., King, S. J., and Gross, S. P. (2008). Tuning microtubule-based transport through filamentous MAPs: the problem of dynein. Traffic 9, 882-892. doi: 10.1111/j.1600-0854.2008.00741.x
272. Vielhaber, S., Jakubiczka, S., Gaul, C., Schoenfeld, M. A., Debska-Vielhaber, G., Zierz, S., et al. (2006). Brain 1H magnetic resonance spectroscopic differences in myotonic dystrophy type 2 and type 1. Muscle Nerve 34, 145-152. doi: 10.1002/mus.20565
273. Villa, C., Fenoglio, C., De Riz, M., Clerici, F., Marcone, A., Benussi, L., et al. (2011). Role of hnRNP-A1 and miR-590-3p in neuronal death: genetics and expression analysis in patients with Alzheimer disease and frontotemporal lobar degeneration. Rejuvenation Res. 14, 275-281. doi: 10.1089/rej.2010.1123
274. Von Bergen, M., Barghorn, S., Li, L., Marx, A., Biernat, J., Mandelkow, E. M., et al. (2001). Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure. J. Biol. Chem. 276, 48165-48174. doi: 10.1074/jbc.M105196200
275. Von Bergen, M., Friedhoff, P., Biernat, J., Heberle, J., Mandelkow, E. M., and Mandelkow, E. (2000). Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure. Proc. Natl. Acad. Sci. U.S.A. 97, 5129-5134. doi: 10.1073/pnas.97.10.5129
276. Voss, K., Combs, B., Patterson, K. R., Binder, L. I., and Gamblin, T. C. (2012). Hsp70 alters tau function and aggregation in an isoform specific manner. Biochemistry 51, 888-898. doi: 10.1021/bi2018078
277. Wang, G. S., Kearney, D. L., De Biasi, M., Taffet, G., and Cooper, T. A. (2007). Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy. J. Clin. Invest. 117, 2802-2811. doi: 10.1172/JCI32308
278. Weber, Y. G., Roebling, R., Kassubek, J., Hoffmann, S., Rosenbohm, A., Wolf, M., et al. (2010). Comparative analysis of brain structure, metabolism, and cognition in myotonic dystrophy 1 and 2. Neurology 74, 1108-1117. doi: 10.1212/WNL.0b013e3181d8c35f
279. Wegiel, J., Kaczmarski, W., Barua, M., Kuchna, I., Nowicki, K., Wang, K. C., et al. (2011). Link between DYRK1A overexpression and several-fold enhancement of neurofibrillary degeneration with 3-repeat tau protein in Down syndrome. J. Neuropathol. Exp. Neurol. 70, 36-50. doi: 10.1097/NEN.0b013e318202bfa1
280. Wei, M. L., and Andreadis, A. (1998). Splicing of a regulated exon reveals additional complexity in the axonal microtubule-associated protein tau. J. Neurochem. 70, 1346-1356. doi: 10.1046/j.1471-4159.1998.70041346.x
281. White, M. C., Gao, R., Xu, W., Mandal, S. M., Lim, J. G., Hazra, T. K., et al. (2010). Inactivation of hnRNP K by expanded intronic AUUCU repeat induces apopto-sis via translocation of PKCdelta to mitochondria in spinocerebellar ataxia 10. PLoS Genet. 6:e1000984. doi: 10.1371/journal.pgen.1000984
282. Wijsman, E. M., Pankratz, N. D., Choi, Y., Rothstein, J. H., Faber, K. M., Cheng, R., et al. (2011). Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. PLoS Genet. 7:e1001308. doi: 10.1371/journal.pgen.1001308
283. Wilburn, B., Rudnicki, D. D., Zhao, J., Weitz, T. M., Cheng, Y., Gu, X., et al. (2011). An antisense CAG repeat transcript at JPH3 locus mediates expanded polyglu-tamine protein toxicity in Huntington's disease-like 2 mice. Neuron 70, 427-440. doi: 10.1016/j.neuron.2011.03.021
284. Wille, H., Drewes, G., Biernat, J., Mandelkow, E. M., and Mandelkow, E. (1992). Alzheimer-like paired helical filaments and antiparallel dimers formed from microtubule-associated protein tau in vitro. J. Cell Biol. 118, 573-584. doi: 10.1083/jcb.118.3.573
285. Winblad, S., Hellstrom, P., Lindberg, C., and Hansen, S. (2006a). Facial emotion recognition in myotonic dystrophy type 1 correlates with CTG repeat expansion. J. Neurol. Neurosurg. Psychiatr. 77, 219-223. doi: 10.1136/jnnp.2005.070763
286. Winblad, S., Lindberg, C., and Hansen, S. (2006b). Cognitive deficits and CTG repeat expansion size in classical myotonic dystrophy type 1 (DM1). Behav. Brain Funct. 2, 16. doi: 10.1186/1744-9081-2-16
287. Winblad, S., Mansson, J. E., Blennow, K., Jensen, C., Samuelsson, L., and Lindberg, C. (2008). Cerebrospinal fluid tau and amyloid beta42 protein in patients with myotonic dystrophy type 1. Eur. J. Neurol. 15, 947-952. doi: 10.1111/j.1468-1331.2008.02217.x
288. Wojciechowska, M., and Krzyzosiak, W. J. (2011). Cellular toxicity of expanded RNA repeats: focus on RNA foci. Hum. Mol. Genet. 20, 3811-3821. doi: 10.1093/hmg/ddr299
289. Wong, J. (2013). Altered expression of RNA splicing proteins in Alzheimer's disease patients: evidence from two microarray studies. Dement. Geriatr. Cogn. Dis. Extra 3, 74-85. doi: 10.1159/000348406
290. Wong, J., Garner, B., Halliday, G. M., and Kwok, J. B. (2012). Srp20 regulates TrkB pre-mRNA splicing to generate TrkB-Shc transcripts with implications for Alzheimer's disease. J. Neurochem. 123, 159-171. doi: 10.1111/j.1471-4159.2012.07873.x
291. Wong, L. J., Ashizawa, T., Monckton, D. G., Caskey, C. T., and Richards, C. S. (1995). Somatic heterogeneity of the CTG repeat in myotonic dystrophy is age and size dependent. Am. J. Hum. Genet. 56, 114-122.
292. Wozniak, J. R., Mueller, B. A., Bell, C. J., Muetzel, R. L., Lim, K. O., and Day, J. W. (2013). Diffusion tensor imaging reveals widespread white matter abnormalities in children and adolescents with myotonic dystrophy type 1. J. Neurol. 260, 1122-1131. doi: 10.1007/s00415-012-6771-4
293. Wu, J. Q., Wang, X., Beveridge, N. J., Tooney, P. A., Scott, R. J., Carr, V. J., et al. (2012). Transcriptome sequencing revealed significant alteration of cortical promoter usage and splicing in schizophrenia. PLoS ONE 7:e36351. doi: 10.1371/journal.pone.0036351
294. Wu, T. Y., and Chen, C. P. (2009). Dual action of memantine in Alzheimer disease: a hypothesis. Taiwan. J. Obstet. Gynecol. 48, 273-277. doi: 10.1016/S1028-4559(09)60303-X
295. Yamazaki, Y., Matsubara, T., Takahashi, T., Kurashige, T., Dohi, E., Hiji, M., et al. (2011). Granulovacuolar degenerations appear in relation to hippocam-pal phosphorylated tau accumulation in various neurodegenerative disorders. PLoS ONE 6:e26996. doi: 10.1371/journal.pone.0026996
296. Yamazaki, Y., Takahashi, T., Hiji, M., Kurashige, T., Izumi, Y., Yamawaki, T., et al. (2010). Immunopositivity for ESCRT-III subunit CHMP2B in granulovacuolar degeneration of neurons in the Alzheimer's disease hippocampus. Neurosci. Lett. 477, 86-90. doi: 10.1016/j.neulet.2010.04.038
297. Yang, L., Embree, L. J., Tsai, S., and Hickstein, D. D. (1998). Oncoprotein TLS interacts with serine-arginine proteins involved in RNA splicing. J. Biol. Chem. 273, 27761-27764. doi: 10.1074/jbc.273.43.27761
298. Yang, Y., Ma, D., Wang, Y., Jiang, T., Hu, S., Zhang, M., et al. (2013). Intranasal insulin ameliorates tau hyperphosphorylation in a rat model of type 2 diabetes. J. Alzheimers. Dis. 33, 329-338. doi: 10.3233/JAD-2012-121294
299. Yoshimura, N., Otake, M., Igarashi, K., Matsunaga, M., Takebe, K., and Kudo, H. (1990). Topography of Alzheimer's neurofibrillary change distribution in myotonic dystrophy. Clin. Neuropathol. 9, 234-239.
300. Zhang, W., Liu, H., Han, K., and Grabowski, P. J. (2002). Region-specific alternative splicing in the nervous system: implications for regulation by the RNA-binding protein NAPOR. RNA 8, 671-685. doi: 10.1017/S1355838202027036
301. Zhang, Z., Lotti, F., Dittmar, K., Younis, I., Wan, L., Kasim, M., et al. (2008). SMN deficiency causes tissue-specific perturbations in the repertoire of snRNAs and widespread defects in splicing. Cell 133, 585-600. doi: 10.1016/j.cell.2008.03.031
302. Zhong, Q., Congdon, E. E., Nagaraja, H. N., and Kuret, J. (2012). Tau isoform composition influences rate and extent of filament formation. J. Biol. Chem. 287, 20711-20719. doi: 10.1074/jbc.M112.364067
303. Zu, T., Gibbens, B., Doty, N. S., Gomes-Pereira, M., Huguet, A., Stone, M. D., et al. (2011). Non-ATG-initiated translation directed by microsatellite expansions. Proc. Natl. Acad. Sci. U.S.A. 108, 260-265. doi: 10.1073/pnas.1013343108
304. Zukin, R. S., and Bennett, M. V. (1995). Alternatively spliced isoforms of the NMDARI receptor subunit. Trends Neurosci. 18, 306-313. doi: 10.1016/0166-2236(95)93920-S