Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins

Journal of Neurochemistry

Volumn , Issue , 2016, Pages 95-111

  Ratti, Antonia ^a,b   Buratti, Emanuele ^c  

^a UNIVERSITY OF MILAN   (Italy)

^b ISTITUTO AUXOLOGICO ITALIANO   (Italy)

^c INTERNATIONAL CENTRE FOR GENETIC ENGINEERING AND BIOTECHNOLOGY   (Italy)

Author keywords

ALS; FTLD; FUS TLS; protein aggregation; RNA binding proteins; TDP 43

Indexed keywords

FUSED IN SARCOMA PROTEIN; LONG UNTRANSLATED RNA; MESSENGER RNA; TAR DNA BINDING PROTEIN; UNTRANSLATED RNA;

AMYOTROPHIC LATERAL SCLEROSIS; DNA DAMAGE; DNA REPAIR; FRONTAL VARIANT FRONTOTEMPORAL DEMENTIA; GAIN OF FUNCTION MUTATION; GENE EXPRESSION; HUMAN; LOSS OF FUNCTION MUTATION; MOLECULAR PATHOLOGY; NONHUMAN; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; RNA METABOLISM; RNA PROCESSING; RNA SPLICING; RNA STABILITY; RNA TRANSLATION; RNA TRANSPORT;

EID: 84981188324     PISSN: 00223042     EISSN: 14714159     Source Type: Journal    
DOI: 10.1111/jnc.13625     Document Type: Review

References (200)

1. Alami N. H., Smith R. B., Carrasco M. A. et al. (2014) Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron 81, 536–543.
2. Arai T., Hasegawa M., Akiyama H. et al. (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun. 351, 602–611.
3. Armstrong G. A. and Drapeau P. (2013) Loss and gain of FUS function impair neuromuscular synaptic transmission in a genetic model of ALS. Hum. Mol. Genet. 22, 4282–4292.
4. Aulas A. and Vande Velde C. (2015) Alterations in stress granule dynamics driven by TDP-43 and FUS: a link to pathological inclusions in ALS? Front. Cell. Neurosci. 9, 423.
5. Avendano-Vazquez S. E., Dhir A., Bembich S., Buratti E., Proudfoot N. and Baralle F. E. (2012) Autoregulation of TDP-43 mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection. Genes Dev. 26, 1679–1684.
6. Ayala Y. M., De Conti L., Avendano-Vazquez S. E. et al. (2011) TDP-43 regulates its mRNA levels through a negative feedback loop. EMBO J. 30, 277–288.
7. Baechtold H., Kuroda M., Sok J., Ron D., Lopez B. S. and Akhmedov A. T. (1999) Human 75-kDa DNA-pairing protein is identical to the pro-oncoprotein TLS/FUS and is able to promote D-loop formation. J. Biol. Chem. 274, 34337–34342.
8. Baloh R. H. (2012) How do the RNA-binding proteins TDP-43 and FUS relate to amyotrophic lateral sclerosis and frontotemporal degeneration, and to each other? Curr. Opin. Neurol. 25, 701–707.
9. Belly A., Moreau-Gachelin F., Sadoul R. and Goldberg Y. (2005) Delocalization of the multifunctional RNA splicing factor TLS/FUS in hippocampal neurones: exclusion from the nucleus and accumulation in dendritic granules and spine heads. Neurosci. Lett. 379, 152–157.
10. Bentmann E., Haass C. and Dormann D. (2013) Stress granules in neurodegeneration–lessons learnt from TAR DNA binding protein of 43 kDa and fused in sarcoma. FEBS J. 280, 4348–4370.
11. Bigio E. H., Wu J. Y., Deng H. X. et al. (2013) Inclusions in frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP) and amyotrophic lateral sclerosis (ALS), but not FTLD with FUS proteinopathy (FTLD-FUS), have properties of amyloid. Acta Neuropathol. 125, 463–465.
12. van Blitterswijk M., Wang E. T., Friedman B. A. et al. (2013) Characterization of FUS mutations in amyotrophic lateral sclerosis using RNA-Seq. PLoS ONE 8, e60788.
13. Blokhuis A. M., Groen E. J., Koppers M., van den Berg L. H. and Pasterkamp R. J. (2013) Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol. 125, 777–794.
14. Bosco D. A., Lemay N., Ko H. K. et al. (2010) Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum. Mol. Genet. 19, 4160–4175.
15. Bose J. K., Wang I. F., Hung L., Tarn W. Y. and Shen C. K. (2008) TDP-43 overexpression enhances exon 7 inclusion during the survival of motor neuron pre-mRNA splicing. J. Biol. Chem. 283, 28852–28859.
16. Buratti E. (2015) Functional significance of TDP-43 mutations in disease. Adv. Genet. 91, 1–53.
17. Buratti E. and Baralle F. E. (2001) Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9. J. Biol. Chem. 276, 36337–36343.
18. Buratti E. and Baralle F. E. (2009) The molecular links between TDP-43 dysfunction and neurodegeneration. Adv. Genet. 66, 1–34.
19. Buratti E. and Baralle F. E. (2012) TDP-43: gumming up neurons through protein-protein and protein-RNA interactions. Trends Biochem. Sci. 37, 237–247.
20. Buratti E., Dork T., Zuccato E., Pagani F., Romano M. and Baralle F. E. (2001) Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J. 20, 1774–1784.
21. Buratti E., De Conti L., Stuani C., Romano M., Baralle M. and Baralle F. (2010) Nuclear factor TDP-43 can affect selected microRNA levels. FEBS J. 277, 2268–2281.
22. Buratti E., Romano M. and Baralle F. E. (2013) TDP-43 high throughput screening analyses in neurodegeneration: advantages and pitfalls. Mol. Cell Neurosci. 56C, 465–474.
23. Busch A. and Hertel K. J. (2012) Evolution of SR protein and hnRNP splicing regulatory factors. Wiley Interdiscip. Rev. RNA 3, 1–12.
24. Calvio C., Neubauer G., Mann M. and Lamond A. I. (1995) Identification of hnRNP P2 as TLS/FUS using electrospray mass spectrometry. RNA 1, 724–733.
25. Campos-Melo D., Droppelmann C. A., Volkening K. and Strong M. J. (2014) RNA-binding proteins as molecular links between cancer and neurodegeneration. Biogerontology 15, 587–610.
26. Capitini C., Conti S., Perni M. et al. (2014) TDP-43 inclusion bodies formed in bacteria are structurally amorphous, non-amyloid and inherently toxic to neuroblastoma cells. PLoS ONE 9, e86720.
27. Casafont I., Bengoechea R., Tapia O., Berciano M. T. and Lafarga M. (2009) TDP-43 localizes in mRNA transcription and processing sites in mammalian neurons. J. Struct. Biol. 167, 235–241.
28. Chang H. Y., Hou S. C., Way T. D., Wong C. H. and Wang I. F. (2013) Heat-shock protein dysregulation is associated with functional and pathological TDP-43 aggregation. Nat. Commun. 4, 2757.
29. Chen A. K., Lin R. Y., Hsieh E. Z., Tu P. H., Chen R. P., Liao T. Y., Chen W., Wang C. H. and Huang J. J. (2010) Induction of amyloid fibrils by the C-terminal fragments of TDP-43 in amyotrophic lateral sclerosis. J. Am. Chem. Soc. 132, 1186–1187.
30. Cirillo D., Agostini F., Klus P., Marchese D., Rodriguez S., Bolognesi B. and Tartaglia G. G. (2013) Neurodegenerative diseases: quantitative predictions of protein-RNA interactions. RNA 19, 129–140.
31. Cohen T. J., Hwang A. W., Restrepo C. R., Yuan C. X., Trojanowski J. Q. and Lee V. M. (2015) An acetylation switch controls TDP-43 function and aggregation propensity. Nat. Commun. 6, 5845.
32. Collins M., Riascos D., Kovalik T. et al. (2012) The RNA-binding motif 45 (RBM45) protein accumulates in inclusion bodies in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) patients. Acta Neuropathol. 124, 717–732.
33. Colombrita C., Zennaro E., Fallini C., Weber M., Sommacal A., Buratti E., Silani V. and Ratti A. (2009) TDP-43 is recruited to stress granules in conditions of oxidative insult. J. Neurochem. 111, 1051–1061.
34. Colombrita C., Onesto E., Megiorni F., Pizzuti A., Baralle F. E., Buratti E., Silani V. and Ratti A. (2012) TDP-43 and FUS RNA-binding proteins bind distinct sets of cytoplasmic messenger RNAs and Differently regulate their post-transcriptional fate in motoneuron-like cells. J. Biol. Chem. 287, 15635–15647.
35. Colombrita C., Onesto E., Buratti E., de la Grange P., Gumina V., Baralle F. E., Silani V. and Ratti A. (2015) From transcriptomic to protein level changes in TDP-43 and FUS loss-of-function cell models. Biochim. Biophys. Acta 1849, 1398–1410.
36. Cooper-Knock J., Walsh M. J., Higginbottom A. et al. (2014) Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain 137, 2040–2051.
37. Costessi L., Porro F., Iaconcig A. and Muro A. F. (2014) TDP-43 regulates beta-adducin (Add2) transcript stability. RNA Biol. 11, 1280–1290.
38. Coyne A. N., Siddegowda B. B., Estes P. S., Johannesmeyer J., Kovalik T., Daniel S. G., Pearson A., Bowser R. and Zarnescu D. C. (2014) Futsch/MAP1B mRNA is a translational target of TDP-43 and is neuroprotective in a Drosophila model of amyotrophic lateral sclerosis. J. Neurosci. 34, 15962–15974.
39. Cragnaz L., Klima R., Skoko N., Budini M., Feiguin F. and Baralle F. E. (2014) Aggregate formation prevents dTDP-43 neurotoxicity in the Drosophila melanogaster eye. Neurobiol. Dis. 71, 74–80.
40. Crozat A., Aman P., Mandahl N. and Ron D. (1993) Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature 363, 640–644.
41. Cushman M., Johnson B. S., King O. D., Gitler A. D. and Shorter J. (2010) Prion-like disorders: blurring the divide between transmissibility and infectivity. J. Cell Sci. 123, 1191–1201.
42. Dammer E. B., Fallini C., Gozal Y. M. et al. (2012) Coaggregation of RNA-binding proteins in a model of TDP-43 proteinopathy with selective RGG motif methylation and a role for RRM1 ubiquitination. PLoS ONE 7, e38658.
43. De Conti L., Akinyi M. V., Mendoza-Maldonado R., Romano M., Baralle M. and Buratti E. (2015) TDP-43 affects splicing profiles and isoform production of genes involved in the apoptotic and mitotic cellular pathways. Nucleic Acids Res. 43, 8990–9005.
44. Deng H., Gao K. and Jankovic J. (2014) The role of FUS gene variants in neurodegenerative diseases. Nat. Rev. Neurol. 10, 337–348.
45. Di Carlo V., Grossi E., Laneve P., Morlando M., Dini Modigliani S., Ballarino M., Bozzoni I. and Caffarelli E. (2013) TDP-43 regulates the microprocessor complex activity during in vitro neuronal differentiation. Mol. Neurobiol. 48, 952–963.
46. Dini Modigliani S., Morlando M., Errichelli L., Sabatelli M. and Bozzoni I. (2014) An ALS-associated mutation in the FUS 3′-UTR disrupts a microRNA-FUS regulatory circuitry. Nat. Commun. 5, 4335.
47. Dormann D. and Haass C. (2011) TDP-43 and FUS: a nuclear affair. Trends Neurosci. 34, 339–348.
48. Dormann D. and Haass C. (2013) Fused in sarcoma (FUS): an oncogene goes awry in neurodegeneration. Mol. Cell Neurosci. 56, 475–486.
49. Dormann D., Rodde R., Edbauer D. et al. (2010) ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J. 29, 2841–2857.
50. Dormann D., Madl T., Valori C. F. et al. (2012) Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS. EMBO J. 31, 4258–4275.
51. Dreyfuss G., Kim V. N. and Kataoka N. (2002) Messenger-RNA-binding proteins and the messages they carry. Nat. Rev. Mol. Cell Biol. 3, 195–205.
52. 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.
53. Fan Z., Chen X. and Chen R. (2014) Transcriptome-wide analysis of TDP-43 binding small RNAs identifies miR-NID1 (miR-8485), a novel miRNA that represses NRXN1 expression. Genomics 103, 76–82.
54. Fang Y. S., Tsai K. J., Chang Y. J. et al. (2014) Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients. Nat. Commun. 5, 4824.
55. Feiler M. S., Strobel B., Freischmidt A. et al. (2015) TDP-43 is intercellularly transmitted across axon terminals. J. Cell Biol. 211, 897–911.
56. Fiesel F. C., Schurr C., Weber S. S. and Kahle P. J. (2011) TDP-43 knockdown impairs neurite outgrowth dependent on its target histone deacetylase 6. Mol. Neurodegener. 6, 64.
57. 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.
58. 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.
59. Fujii R. and Takumi T. (2005) TLS facilitates transport of mRNA encoding an actin-stabilizing protein to dendritic spines. J. Cell Sci. 118, 5755–5765.
60. Fujii R., Okabe S., Urushido T., Inoue K., Yoshimura A., Tachibana T., Nishikawa T., Hicks G. G. and Takumi T. (2005) The RNA binding protein TLS is translocated to dendritic spines by mGluR5 activation and regulates spine morphology. Curr. Biol. 15, 587–593.
61. Furukawa Y., Kaneko K., Watanabe S., Yamanaka K. and Nukina N. (2011) A seeding reaction recapitulates intracellular formation of Sarkosyl-insoluble transactivation response element (TAR) DNA-binding protein-43 inclusions. J. Biol. Chem. 286, 18664–18672.
62. Gardiner M., Toth R., Vandermoere F., Morrice N. A. and Rouse J. (2008) Identification and characterization of FUS/TLS as a new target of ATM. Biochem. J. 415, 297–307.
63. Gerbino V., Carri M. T., Cozzolino M. and Achsel T. (2013) Mislocalised FUS mutants stall spliceosomal snRNPs in the cytoplasm. Neurobiol. Dis. 55, 120–128.
64. Gerstberger S., Hafner M., Ascano M. and Tuschl T. (2014) Evolutionary conservation and expression of human RNA-binding proteins and their role in human genetic disease. Adv. Exp. Med. Biol. 825, 1–55.
65. Gitcho M. A., Baloh R. H., Chakraverty S. et al. (2008) TDP-43 A315T mutation in familial motor neuron disease. Ann. Neurol. 63, 535–538.
66. Godena V. K., Romano G., Romano M., Appocher C., Klima R., Buratti E., Baralle F. E. and Feiguin F. (2011) TDP-43 regulates Drosophila neuromuscular junctions growth by modulating Futsch/MAP1B levels and synaptic microtubules organization. PLoS ONE 6, e17808.
67. Golde T. E. (2009) The therapeutic importance of understanding mechanisms of neuronal cell death in neurodegenerative disease. Mol. Neurodegener. 4, 8.
68. Goodall E. F., Heath P. R., Bandmann O., Kirby J. and Shaw P. J. (2013) Neuronal dark matter: the emerging role of microRNAs in neurodegeneration. Front. Cell. Neurosci. 7, 178.
69. Grammatikakis I., Panda A. C., Abdelmohsen K. and Gorospe M. (2014) Long noncoding RNAs(lncRNAs) and the molecular hallmarks of aging. Aging (Albany NY) 6, 992–1009.
70. Gregory R. I., Yan K. P., Amuthan G., Chendrimada T., Doratotaj B., Cooch N. and Shiekhattar R. (2004) The Microprocessor complex mediates the genesis of microRNAs. Nature 432, 235–240.
71. Guo W., Chen Y., Zhou X. et al. (2011) An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity. Nat. Struct. Mol. Biol. 18, 822–830.
72. Guo F., Jiao F., Song Z., Li S., Liu B., Yang H., Zhou Q. and Li Z. (2015) Regulation of MALAT1 expression by TDP43 controls the migration and invasion of non-small cell lung cancer cells in vitro. Biochem. Biophys. Res. Commun. 465, 293–298.
73. Halliday G., Bigio E. H., Cairns N. J., Neumann M., Mackenzie I. R. and Mann D. M. (2012) Mechanisms of disease in frontotemporal lobar degeneration: gain of function versus loss of function effects. Acta Neuropathol. 124, 373–382.
74. Hardy J. and Rogaeva E. (2014) Motor neuron disease and frontotemporal dementia: sometimes related, sometimes not. Exp. Neurol. 262(Pt B), 75–83.
75. Hicks G. G., Singh N., Nashabi A. et al. (2000) Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death. Nat. Genet. 24, 175–179.
76. Higashi S., Kabuta T., Nagai Y., Tsuchiya Y., Akiyama H. and Wada K. (2013) TDP-43 associates with stalled ribosomes and contributes to cell survival during cellular stress. J. Neurochem. 126, 288–300.
77. Hoell J. I., Larsson E., Runge S. et al. (2011) RNA targets of wild-type and mutant FET family proteins. Nat. Struct. Mol. Biol. 18, 1428–1431.
78. Honda D., Ishigaki S., Iguchi Y., Fujioka Y., Udagawa T., Masuda A., Ohno K., Katsuno M. and Sobue G. (2013) The ALS/FTLD-related RNA-binding proteins TDP-43 and FUS have common downstream RNA targets in cortical neurons. FEBS Open. Bio. 4, 1–10.
79. Ichikawa H., Shimizu K., Hayashi Y. and Ohki M. (1994) An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation. Cancer Res. 54, 2865–2868.
80. Ishigaki S., Masuda A., Fujioka Y., Iguchi Y., Katsuno M., Shibata A., Urano F., Sobue G. and Ohno K. (2012) Position-dependent FUS-RNA interactions regulate alternative splicing events and transcriptions. Sci. Rep. 2, 529.
81. Johnson B. S., Snead D., Lee J. J., McCaffery J. M., Shorter J. and Gitler A. D. (2009) TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J. Biol. Chem. 284, 20329–20339.
82. Johnson J. O., Pioro E. P., Boehringer A. et al. (2014) Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat. Neurosci. 17, 664–666.
83. Kabashi E., Valdmanis P. N., Dion P. et al. (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572–574.
84. Kabashi E., Bercier V., Lissouba A., Liao M., Brustein E., Rouleau G. A. and Drapeau P. (2011) FUS and TARDBP but not SOD1 interact in genetic models of amyotrophic lateral sclerosis. PLoS Genet. 7, e1002214.
85. Kao P. F., Chen Y. R., Liu X. B., DeCarli C., Seeley W. W. and Jin L. W. (2015) Detection of TDP-43 oligomers in frontotemporal lobar degeneration-TDP. Ann. Neurol. 78, 211–221.
86. 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. USA 109, 3347–3352.
87. Kim S. H., Shanware N. P., Bowler M. J. and Tibbetts R. S. (2010) Amyotrophic lateral sclerosis-associated proteins TDP-43 and FUS/TLS function in a common biochemical complex to co-regulate HDAC6 mRNA. J. Biol. Chem. 285, 34097–34105.
88. Kim H. J., Kim N. C., Wang Y. D. et al. (2013) Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495, 467–473.
89. King I. N., Yartseva V., Salas D. et al. (2014) The RNA-binding protein TDP-43 selectively disrupts microRNA-1/206 incorporation into the RNA-induced silencing complex. J. Biol. Chem. 289, 14263–14271.
90. Kino Y., Washizu C., Kurosawa M. et al. (2015) FUS/TLS deficiency causes behavioral and pathological abnormalities distinct from amyotrophic lateral sclerosis. Acta Neuropathol. Commun. 3, 24.
91. Kryndushkin D., Wickner R. B. and Shewmaker F. (2011) FUS/TLS forms cytoplasmic aggregates, inhibits cell growth and interacts with TDP-43 in a yeast model of amyotrophic lateral sclerosis. Protein Cell 2, 223–236.
92. Kwiatkowski T. J., Jr, Bosco D. A., Leclerc A. L. et al. (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323, 1205–1208.
93. Lagier-Tourenne C., Polymenidou M., Hutt K. R. 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.
94. Lanson N. A., Jr, Maltare A., King H., Smith R., Kim J. H., Taylor J. P., Lloyd T. E. and Pandey U. B. (2011) A Drosophila model of FUS-related neurodegeneration reveals genetic interaction between FUS and TDP-43. Hum. Mol. Genet. 20, 2510–2523.
95. Lattante S., Rouleau G. A. and Kabashi E. (2013) TARDBP and FUS mutations associated with amyotrophic lateral sclerosis: summary and update. Hum. Mutat. 34, 812–826.
96. Lee S. and Kim H. J. (2015) Prion-like mechanism in amyotrophic lateral sclerosis: are protein aggregates the key? Exp. Neurobiol. 24, 1–7.
97. Lee E. B., Lee V. M. and Trojanowski J. Q. (2012) Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat. Rev. Neurosci. 13, 38–50.
98. Lee Y. B., Chen H. J., Peres J. N. et al. (2013) Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep. 5, 1178–1186.
99. Lee S., Lee T. A., Lee E. et al. (2015) Identification of a subnuclear body involved in sequence-specific cytokine RNA processing. Nat. Commun. 6, 5791.
100. Leitman J., Ulrich Hartl F. and Lederkremer G. Z. (2013) Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress. Nat. Commun. 4, 2753.
101. Li W., Jin Y., Prazak L., Hammell M. and Dubnau J. (2012) Transposable elements in TDP-43-mediated neurodegenerative disorders. PLoS ONE 7, e44099.
102. Li Y. R., King O. D., Shorter J. and Gitler A. D. (2013) Stress granules as crucibles of ALS pathogenesis. J. Cell Biol. 201, 361–372.
103. Li P., Ruan X., Yang L. et al. (2015a) A liver-enriched long non-coding RNA, lncLSTR, regulates systemic lipid metabolism in mice. Cell Metab. 21, 455–467.
104. Li Y., Collins M., Geiser R., Bakkar N., Riascos D. and Bowser R. (2015b) RBM45 homo-oligomerization mediates association with ALS-linked proteins and stress granules. Sci. Rep. 5, 14262.
105. Ling S. C., Albuquerque C. P., Han J. S., Lagier-Tourenne C., Tokunaga S., Zhou H. and Cleveland D. W. (2010) ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS. Proc. Natl Acad. Sci. USA 107, 13318–13323.
106. Ling S. C., Polymenidou M. and Cleveland D. W. (2013) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79, 416–438.
107. Liu X., Li D., Zhang W., Guo M. and Zhan Q. (2012) Long non-coding RNA gadd7 interacts with TDP-43 and regulates Cdk6 mRNA decay. EMBO J. 31, 4415–4427.
108. Lourenco G. F., Janitz M., Huang Y. and Halliday G. M. (2015) Long noncoding RNAs in TDP-43 and FUS/TLS-related frontotemporal lobar degeneration (FTLD). Neurobiol. Dis. 82, 445–454.
109. Lukavsky P. J., Daujotyte D., Tollervey J. R., Ule J., Stuani C., Buratti E., Baralle F. E., Damberger F. F. and Allain F. H. (2013) Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43. Nat. Struct. Mol. Biol. 20, 1443–1449.
110. Mackenzie I. R. and Neumann M. (2012) FET proteins in frontotemporal dementia and amyotrophic lateral sclerosis. Brain Res. 1462, 40–43.
111. Mackenzie I. R., Bigio E. H., Ince P. G. et al. (2007) Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann. Neurol. 61, 427–434.
112. Mackenzie I. R., Rademakers R. and Neumann M. (2010) TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 9, 995–1007.
113. MacNair L., Xiao S., Miletic D., Ghani M., Julien J. P., Keith J., Zinman L., Rogaeva E. and Robertson J. (2015) MTHFSD and DDX58 are novel RNA-binding proteins abnormally regulated in amyotrophic lateral sclerosis. Brain 139, 86–100.
114. Majumder P., Chen Y. T., Bose J. K. et al. (2012) TDP-43 regulates the mammalian spinogenesis through translational repression of Rac1. Acta Neuropathol. 124, 231–245.
115. Mastrocola A. S., Kim S. H., Trinh A. T., Rodenkirch L. A. and Tibbetts R. S. (2013) The RNA-binding protein fused in sarcoma (FUS) functions downstream of poly(ADP-ribose) polymerase (PARP) in response to DNA damage. J. Biol. Chem. 288, 24731–24741.
116. Masuda A., Takeda J., Okuno T., Okamoto T., Ohkawara B., Ito M., Ishigaki S., Sobue G. and Ohno K. (2015) Position-specific binding of FUS to nascent RNA regulates mRNA length. Genes Dev. 29, 1045–1057.
117. McDonald K. K., Aulas A., Destroismaisons L., Pickles S., Beleac E., Camu W., Rouleau G. A. and Vande Velde C. (2011) TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1. Hum. Mol. Genet. 20, 1400–1410.
118. Mohagheghi F., Prudencio M., Stuani C., Cook C., Jansen-West K., Dickson D. W., Petrucelli L. and Buratti E. (2015) TDP-43 functions within a network of hnRNP proteins to inhibit the production of a truncated human SORT1 receptor. Hum. Mol. Genet. 25, 534–545.
119. Mompean M., Buratti E., Guarnaccia C., Brito R. M., Chakrabartty A., Baralle F. E. and Laurents D. V. (2014) Structural characterization of the minimal segment of TDP-43 competent for aggregation. Arch. Biochem. Biophys. 545C, 53–62.
120. Mompean M., Hervas R., Xu Y. et al. (2015) Structural evidence of amyloid fibril formation in the putative aggregation domain of TDP-43. J. Phys. Chem. Lett. 6, 2608–2615.
121. Mori K., Lammich S., Mackenzie I. R. et al. (2013) hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations. Acta Neuropathol. 125, 413–423.
122. Morlando M., Dini Modigliani S., Torrelli G., Rosa A., Di Carlo V., Caffarelli E. and Bozzoni I. (2012) FUS stimulates microRNA biogenesis by facilitating co-transcriptional Drosha recruitment. EMBO J. 31, 4502–4510.
123. Morohoshi F., Ootsuka Y., Arai K., Ichikawa H., Mitani S., Munakata N. and Ohki M. (1998) Genomic structure of the human RBP56/hTAFII68 and FUS/TLS genes. Gene 221, 191–198.
124. Muresan V. and Ladescu Muresan Z. (2016) Shared molecular mechanisms in Alzheimer's disease and amyotrophic lateral sclerosis: neurofilament-dependent transport of sAPP, FUS, TDP-43 and SOD1, with endoplasmic reticulum-like tubules. Neurodegener. Dis. 16, 55–61.
125. 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.
126. Narayanan R. K., Mangelsdorf M., Panwar A., Butler T. J., Noakes P. G. and Wallace R. H. (2013) Identification of RNA bound to the TDP-43 ribonucleoprotein complex in the adult mouse brain. Amyotroph. Lateral Scler. Frontotemporal Degener. 14, 252–260.
127. Neumann M. (2013) Frontotemporal lobar degeneration and amyotrophic lateral sclerosis: molecular similarities and differences. Rev. Neurol. (Paris) 169, 793–798.
128. Neumann M., Sampathu D. M., Kwong L. K. et al. (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133.
129. Neumann M., Rademakers R., Roeber S., Baker M., Kretzschmar H. A. and Mackenzie I. R. (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132, 2922–2931.
130. Neumann M., Bentmann E., Dormann D. et al. (2011) FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations. Brain 134, 2595–2609.
131. Nishimoto Y., Nakagawa S., Hirose T. et al. (2013) The long non-coding RNA nuclear-enriched abundant transcript 1_2 induces paraspeckle formation in the motor neuron during the early phase of amyotrophic lateral sclerosis. Mol. Brain. 6, 31.
132. Nishimura A. L., Zupunski V., Troakes C. et al. (2010) Nuclear import impairment causes cytoplasmic trans-activation response DNA-binding protein accumulation and is associated with frontotemporal lobar degeneration. Brain 133, 1763–1771.
133. Nonaka T., Masuda-Suzukake M., Arai T. et al. (2013) Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep. 4, 124–134.
134. Nussbacher J. K., Batra R., Lagier-Tourenne C. and Yeo G. W. (2015) RNA-binding proteins in neurodegeneration: Seq and you shall receive. Trends Neurosci. 38, 226–236.
135. Orozco D. and Edbauer D. (2013) FUS-mediated alternative splicing in the nervous system: consequences for ALS and FTLD. J. Mol. Med. (Berl) 91, 1343–1354.
136. Park Y. Y., Kim S. B., Han H. D. et al. (2013) Tat-activating regulatory DNA-binding protein regulates glycolysis in hepatocellular carcinoma by regulating the platelet isoform of phosphofructokinase through microRNA 520. Hepatology 58, 182–191.
137. Polymenidou M. and Cleveland D. W. (2012) Prion-like spread of protein aggregates in neurodegeneration. J. Exp. Med. 209, 889–893.
138. Polymenidou M., Lagier-Tourenne C., Hutt K. R. et al. (2011) Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat. Neurosci. 14, 459–468.
139. Pradat P. F., Kabashi E. and Desnuelle C. (2015) Deciphering spreading mechanisms in amyotrophic lateral sclerosis: clinical evidence and potential molecular processes. Curr. Opin. Neurol. 28, 455–461.
140. Prudencio M., Jansen-West K. R., Lee W. C. et al. (2012) Misregulation of human sortilin splicing leads to the generation of a nonfunctional progranulin receptor. Proc. Natl Acad. Sci. USA 109, 21510–21515.
141. Raczynska K. D., Ruepp M. D., Brzek A. et al. (2015) FUS/TLS contributes to replication-dependent histone gene expression by interaction with U7 snRNPs and histone-specific transcription factors. Nucleic Acids Res. 43, 9711–9728.
142. Renoux A. J. and Todd P. K. (2012) Neurodegeneration the RNA way. Prog. Neurobiol. 97, 173–189.
143. Roberts T. C., Morris K. V. and Wood M. J. (2014) The role of long non-coding RNAs in neurodevelopment, brain function and neurological disease. Philos. Trans. R. Soc. Lond. B Biol. Sci. 369(1652). pii: 20130507.
144. Robinson J. L., Geser F., Stieber A., Umoh M., Kwong L. K., Van Deerlin V. M., Lee V. M. and Trojanowski J. Q. (2013) TDP-43 skeins show properties of amyloid in a subset of ALS cases. Acta Neuropathol. 125, 121–131.
145. Rogelj B., Easton L. E., Bogu G. K. et al. (2012) Widespread binding of FUS along nascent RNA regulates alternative splicing in the brain. Sci. Rep. 2, 603.
146. Romano M., Feiguin.F., and Buratti E. (2016) TBPH/TDP-43 modulates translation of Drosophila futsch mRNA through an UG-rich sequence within its 5′UTR. Brain Res. pii: S0006-8993(16)30081-6.
147. Rulten S. L., Rotheray A., Green R. L., Grundy G. J., Moore D. A., Gomez-Herreros F., Hafezparast M. and Caldecott K. W. (2014) PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage. Nucleic Acids Res. 42, 307–314.
148. Saini A. and Chauhan V. S. (2011) Delineation of the core aggregation sequences of TDP-43 C-terminal fragment. ChemBioChem 12, 2495–2501.
149. Saini A. and Chauhan V. S. (2014) Self-assembling properties of peptides derived from TDP-43 C-terminal fragment. Langmuir 30, 3845–3856.
150. Scaramuzzino C., Monaghan J., Milioto C. et al. (2013) Protein arginine methyltransferase 1 and 8 interact with FUS to modify its sub-cellular distribution and toxicity in vitro and in vivo. PLoS ONE 8, e61576.
151. Schwartz J. C., Ebmeier C. C., Podell E. R., Heimiller J., Taatjes D. J. and Cech T. R. (2012) FUS binds the CTD of RNA polymerase II and regulates its phosphorylation at Ser2. Genes Dev. 26, 2690–2695.
152. Schwartz J. C., Podell E. R., Han S. S., Berry J. D., Eggan K. C. and Cech T. R. (2014) FUS is sequestered in nuclear aggregates in ALS patient fibroblasts. Mol. Biol. Cell 25, 2571–2578.
153. Sephton C. F. and Yu G. (2015) The function of RNA-binding proteins at the synapse: implications for neurodegeneration. Cell. Mol. Life Sci. 72, 3621–3635.
154. Sephton C. F., Good S. K., Atkin S., Dewey C. M., Mayer P., 3rd, Herz J. and Yu G. (2010) TDP-43 Is a developmentally regulated protein essential for early embryonic development. J. Biol. Chem. 285, 6826–6834.
155. Sephton C. F., Cenik C., Kucukural A. et al. (2011) Identification of neuronal RNA targets of TDP-43-containing ribonucleoprotein complexes. J. Biol. Chem. 286, 1204–1215.
156. Seyfried N. T., Gozal Y. M., Dammer E. B., Xia Q., Duong D. M., Cheng D., Lah J. J., Levey A. I. and Peng J. (2010) Multiplex SILAC analysis of a cellular TDP-43 proteinopathy model reveals protein inclusions associated with SUMOylation and diverse polyubiquitin chains. Mol. Cell Proteomics 9, 705–718.
157. Shelkovnikova T. A. (2013) Modelling FUSopathies: focus on protein aggregation. Biochem. Soc. Trans. 41, 1613–1617.
158. Shelkovnikova T. A., Peters O. M., Deykin A. V. et al. (2013a) Fused in sarcoma (FUS) protein lacking nuclear localization signal (NLS) and major RNA binding motifs triggers proteinopathy and severe motor phenotype in transgenic mice. J. Biol. Chem. 288, 25266–25274.
159. Shelkovnikova T. A., Robinson H. K., Connor-Robson N. and Buchman V. L. (2013b) Recruitment into stress granules prevents irreversible aggregation of FUS protein mislocalized to the cytoplasm. Cell Cycle 12, 3194–3202.
160. Shelkovnikova T. A., Robinson H. K., Troakes C., Ninkina N. and Buchman V. L. (2014) Compromised paraspeckle formation as a pathogenic factor in FUSopathies. Hum. Mol. Genet. 23, 2298–2312.
161. Shiga A., Ishihara T., Miyashita A. et al. (2012) Alteration of POLDIP3 splicing associated with loss of function of TDP-43 in tissues affected with ALS. PLoS ONE 7, e43120.
162. Shodai A., Morimura T., Ido A. et al. (2013) Aberrant assembly of RNA recognition motif 1 links to pathogenic conversion of TAR DNA-binding protein of 43 kDa (TDP-43). J. Biol. Chem. 288, 14886–14905.
163. Smethurst P., Sidle K. C. and Hardy J. (2015) Review: prion-like mechanisms of transactive response DNA binding protein of 43 kDa (TDP-43) in amyotrophic lateral sclerosis (ALS). Neuropathol. Appl. Neurobiol. 41, 578–597.
164. Sreedharan J., Blair I. P., Tripathi V. B. et al. (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668–1672.
165. Stalekar M., Yin X., Rebolj K., Darovic S., Troakes C., Mayr M., Shaw C. E. and Rogelj B. (2015) Proteomic analyses reveal that loss of TDP-43 affects RNA processing and intracellular transport. Neuroscience 293, 157–170.
166. Stallings N. R., Puttaparthi K., Dowling K. J., Luther C. M., Burns D. K., Davis K. and Elliott J. L. (2013) TDP-43, an ALS linked protein, regulates fat deposition and glucose homeostasis. PLoS ONE 8, e71793.
167. Strong M. J., Volkening K., Hammond R., Yang W., Strong W., Leystra-Lantz C. and Shoesmith C. (2007) TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol. Cell Neurosci. 35, 320–327.
168. Sun Z., Diaz Z., Fang X., Hart M. P., Chesi A., Shorter J. and Gitler A. D. (2011) Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS. PLoS Biol. 9, e1000614.
169. Sun C. S., Wang C. Y., Chen B. P., He R. Y., Liu G. C., Wang C. H., Chen W., Chern Y. and Huang J. J. (2014) The influence of pathological mutations and proline substitutions in TDP-43 glycine-rich peptides on its amyloid properties and cellular toxicity. PLoS ONE 9, e103644.
170. Sun S., Ling S. C., Qiu J. et al. (2015) ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP. Nat. Commun. 6, 6171.
171. Swanger S. A. and Bassell G. J. (2011) Making and breaking synapses through local mRNA regulation. Curr. Opin. Genet. Dev. 21, 414–421.
172. Tan C. F., Eguchi H., Tagawa A., Onodera O., Iwasaki T., Tsujino A., Nishizawa M., Kakita A. and Takahashi H. (2007) TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation. Acta Neuropathol. (Berl) 113, 535–542.
173. Tollervey J. R., Curk T., Rogelj B. et al. (2011a) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat. Neurosci. 14, 452–458.
174. Tollervey J. R., Wang Z., Hortobagyi T. et al. (2011b) Analysis of alternative splicing associated with aging and neurodegeneration in the human brain. Genome Res. 21, 1572–1582.
175. Tradewell M. L., Yu Z., Tibshirani M., Boulanger M. C., Durham H. D. and Richard S. (2012) Arginine methylation by PRMT1 regulates nuclear-cytoplasmic localization and toxicity of FUS/TLS harbouring ALS-linked mutations. Hum. Mol. Genet. 21, 136–149.
176. Tsuiji H., Iguchi Y., Furuya A. et al. (2013) Spliceosome integrity is defective in the motor neuron diseases ALS and SMA. EMBO Mol. Med. 5, 221–234.
177. Udagawa T., Fujioka Y., Tanaka M. et al. (2015) FUS regulates AMPA receptor function and FTLD/ALS-associated behaviour via GluA1 mRNA stabilization. Nat. Commun. 6, 7098.
178. Vance C., Rogelj B., Hortobagyi T. et al. (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323, 1208–1211.
179. Vanden Broeck L., Callaerts P. and Dermaut B. (2014) TDP-43-mediated neurodegeneration: towards a loss-of-function hypothesis? Trends Mol. Med. 20, 66–71.
180. Vanderweyde T., Youmans K., Liu-Yesucevitz L. and Wolozin B. (2013) Role of stress granules and RNA-binding proteins in neurodegeneration: a mini-review. Gerontology 59, 524–533.
181. Volonte C., Apolloni S. and Parisi C. (2015) MicroRNAs: newcomers into the ALS picture. CNS Neurol. Disord. Drug Targets 14, 194–207.
182. Wang I. F., Wu L. S., Chang H. Y. and Shen C. K. (2008a) TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor. J. Neurochem. 105, 797–806.
183. Wang X., Arai S., Song X. et al. (2008b) Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature 454, 126–130.
184. Wang J. W., Brent J. R., Tomlinson A., Shneider N. A. and McCabe B. D. (2011) The ALS-associated proteins FUS and TDP-43 function together to affect Drosophila locomotion and life span. J. Clin. Invest. 121, 4118–4126.
185. Wang W. Y., Pan L., Su S. C., Quinn E. J., Sasaki M., Jimenez J. C., Mackenzie I. R., Huang E. J. and Tsai L. H. (2013) Interaction of FUS and HDAC1 regulates DNA damage response and repair in neurons. Nat. Neurosci. 16, 1383–1391.
186. Wang X., Schwartz J. C. and Cech T. R. (2015) Nucleic acid-binding specificity of human FUS protein. Nucleic Acids Res. 43, 7535–7543.
187. Wegorzewska I. and Baloh R. H. (2011) TDP-43-based animal models of neurodegeneration: new insights into ALS pathology and pathophysiology. Neurodegener. Dis. 8, 262–274.
188. Woerner A. C., Frottin F., Hornburg D. et al. (2015) Cytoplasmic protein aggregates interfere with nucleo-cytoplasmic transport of protein and RNA. Science 351, 173–176.
189. Xiao S., Sanelli T., Dib S. et al. (2011) RNA targets of TDP-43 identified by UV-CLIP are deregulated in ALS. Mol. Cell Neurosci. 47, 167–180.
190. Xu Z. S. (2012) Does a loss of TDP-43 function cause neurodegeneration? Mol. Neurodegener. 7, 27.
191. Yamaguchi A. and Kitajo K. (2012) The effect of PRMT1-mediated arginine methylation on the subcellular localization, stress granules, and detergent-insoluble aggregates of FUS/TLS. PLoS ONE 7, e49267.
192. Yamazaki T., Chen S., Yu Y. et al. (2012) FUS-SMN protein interactions link the motor neuron diseases ALS and SMA. Cell Rep. 2, 799–806.
193. Yang L., Gal J., Chen J. and Zhu H. (2014) Self-assembled FUS binds active chromatin and regulates gene transcription. Proc. Natl Acad. Sci. USA 111, 17809–17814.
194. Yasuda K., Zhang H., Loiselle D., Haystead T., Macara I. G. and Mili S. (2013) The RNA-binding protein Fus directs translation of localized mRNAs in APC-RNP granules. J. Cell Biol. 203, 737–746.
195. Yoshimura A., Fujii R., Watanabe Y., Okabe S., Fukui K. and Takumi T. (2006) Myosin-Va facilitates the accumulation of mRNA/protein complex in dendritic spines. Curr. Biol. 16, 2345–2351.
196. Yu Y. and Reed R. (2015) FUS functions in coupling transcription to splicing by mediating an interaction between RNAP II and U1 snRNP. Proc. Natl Acad. Sci. USA 112, 8608–8613.
197. Yu Y., Chi B., Xia W. et al. (2015) U1 snRNP is mislocalized in ALS patient fibroblasts bearing NLS mutations in FUS and is required for motor neuron outgrowth in zebrafish. Nucleic Acids Res. 43, 3208–3218.
198. Zeineddine R., Pundavela J. F., Corcoran L. et al. (2015) SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation. Mol. Neurodegener. 10, 57.
199. Zhang Z., Almeida S., Lu Y. et al. (2013) Downregulation of microRNA-9 in iPSC-derived neurons of FTD/ALS patients with TDP-43 mutations. PLoS ONE 8, e76055.
200. Zhou Y., Liu S., Liu G., Ozturk A. and Hicks G. G. (2013) ALS-associated FUS mutations result in compromised FUS alternative splicing and autoregulation. PLoS Genet. 9, e1003895.