Emerging pathogenic pathways in the spinocerebellar ataxias

Current Opinion in Genetics and Development

Volumn 19, Issue 3, 2009, Pages 247-253

  Carlson, Kerri M ^a   Andresen, J Michael ^a,b   Orr, Harry T ^a,b  

^a UNIVERSITY OF MINNESOTA   (United States)

^b UNIVERSITY OF MINNESOTA MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMPA RECEPTOR; ATAXIN 1; ATAXIN 3; ATAXIN 7; CALCIUM; EXCITATORY AMINO ACID TRANSPORTER 4; FIBROBLAST GROWTH FACTOR 14; GLUTAMIC ACID; POLYGLUTAMINE; PROTEIN KINASE C DELTA; RETINOIC ACID RECEPTOR ALPHA; RNA; SARCOPLASMIC RETICULUM CALCIUM TRANSPORTING ADENOSINE TRIPHOSPHATASE; SILENCING MEDIATOR OF RETINOID AND THYROID HORMONE RECEPTOR; TATA BINDING PROTEIN; TRANSCRIPTION FACTOR IIB;

AUTOSOMAL DOMINANT INHERITANCE; CALCIUM SIGNALING; GENE DELETION; GENE EXPRESSION; GENE IDENTIFICATION; GENE MUTATION; HUMAN; NERVE DEGENERATION; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; RNA PROCESSING; RNA TRANSCRIPTION; SIGNAL TRANSDUCTION; SPINOCEREBELLAR DEGENERATION; SYNAPTIC TRANSMISSION; TRANSCRIPTION REGULATION;

ANIMALS; HUMANS; MODELS, BIOLOGICAL; MULTIGENE FAMILY; MUTATION; NERVE TISSUE PROTEINS; PURKINJE CELLS; SIGNAL TRANSDUCTION; SPINOCEREBELLAR ATAXIAS;

EID: 68649121647     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.gde.2009.02.009     Document Type: Review

References (47)

1. Duenas A.M., Goold R., and Giunti P. Molecular pathogenesis of spinocerebellar ataxias. Brain 129 (2006) 1357-1370
2. Soong B.W., and Paulson H.L. Spinocerebellar ataxias: an update. Curr Opin Neurol 20 (2007) 438-446
3. Dudding T.E., Friend K., Schofield P.W., Lee S., Wilkinson I.A., and Richards R.I. Autosomal dominant congenital non-progressive ataxia overlaps with the SCA15 locus. Neurology 63 (2004) 2288-2292
4. Jen J.C., Lee H., Cha Y.H., Nelson S.F., and Baloh R.W. Genetic heterogeneity of autosomal dominant nonprogressive congenital ataxia. Neurology 67 (2006) 1704-1706
5. Iwaki A., Kawano Y., Miura S., Shibata H., Matsuse D., Li W., Furuya H., Ohyagi Y., Taniwaki T., Kira J., et al. Heterozygous deletion of ITPR1, but not SUMF1, in spinocerebellar ataxia type 16. J Med Genet 45 (2008) 32-35
6. Storey E., Bahlo M., Fahey M.C., Sisson O., Lueck C.J., and Gardner R.M. A new dominantly-inherited pure cerebellar ataxia, SCA 30. J Neurol Neurosurg Psychiatry 80 (2008) 408-411
7. Helmlinger D., Tora L., and Devys D. Transcriptional alterations and chromatin remodeling in polyglutamine diseases. Trends Genet 22 (2006) 562-570
8. ••], this paper further supports the idea that SCA neuropathology may partly be due to altered interactions with native binding partners.
9. ••], the authors of this paper demonstrate that polyglutamine expansion of TBP decreases its ability to bind promoter DNA. In vivo, mutant TBP that is not able to bind DNA causes a more severe SCA17 phenotype. Together, these data suggest DNA binding of TBP is not necessary for mutant TBP to cause toxic effects in the cell.
10. McMahon S.J., Pray-Grant M.G., Schieltz D., Yates III J.R., and Grant P.A. Polyglutamine-expanded spinocerebellar ataxia-7 protein disrupts normal SAGA and SLIK histone acetyltransferase activity. Proc Natl Acad Sci U S A 102 (2005) 8478-8482
11. Palhan V.B., Chen S., Peng G.H., Tjernberg A., Gamper A.M., Fan Y., Chait B.T., La Spada A.R., and Roeder R.G. Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration. Proc Natl Acad Sci U S A 102 (2005) 8472-8477
12. Helmlinger D., Hardy S., Abou-Sleymane G., Eberlin A., Bowman A.B., Gansmuller A., Picaud S., Zoghbi H.Y., Trottier Y., Tora L., et al. Glutamine-expanded ataxin-7 alters TFTC/STAGA recruitment and chromatin structure leading to photoreceptor dysfunction. PLoS Biol 4 (2006) e67
13. Kohler A., Schneider M., Cabal G.G., Nehrbass U., and Hurt E. Yeast Ataxin-7 links histone deubiquitination with gene gating and mRNA export. Nat Cell Biol 10 (2008) 707-715
14. Lam Y.C., Bowman A.B., Jafar-Nejad P., Lim J., Richman R., Fryer J.D., Hyun E.D., Duvick L.A., Orr H.T., Botas J., et al. ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. Cell 127 (2006) 1335-1347
15. Lim J., Crespo-Barreto J., Jafar-Nejad P., Bowman A.B., Richman R., Hill D.E., Orr H.T., and Zoghbi H.Y. Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 452 (2008) 713-718. This paper used gel filtration chromatography of mouse brain lysates to identify two native protein complexes containing ATXN1: ATXN1/CIC and ATXN1/RBM17. Mutant ATXN1 favors the formation of the RBM17 complexes and leads to a decrease in the CIC complexes. These data suggest that SCA1 pathology is the result of both a gain and loss of ATXN1 function.
16. Serra H.G., Duvick L., Zu T., Carlson K., Stevens S., Jorgensen N., Lysholm A., Burright E., Zoghbi H.Y., Clark H.B., et al. RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell 127 (2006) 697-708
17. Hamilton B.A., Frankel W.N., Kerrebrock A.W., Hawkins T.L., FitzHugh W., Kusumi K., Russell L.B., Mueller K.L., van Berkel V., Birren B.W., et al. Disruption of the nuclear hormone receptor RORalpha in staggerer mice. Nature 379 (1996) 736-739
18. Ralser M., Albrecht M., Nonhoff U., Lengauer T., Lehrach H., and Krobitsch S. An integrative approach to gain insights into the cellular function of human ataxin-2. J Mol Biol 346 (2005) 203-214
19. Satterfield T.F., and Pallanck L.J. Ataxin-2 and its Drosophila homolog, ATX2, physically assemble with polyribosomes. Hum Mol Genet 15 (2006) 2523-2532
20. Bichelmeier U., Schmidt T., Hubener J., Boy J., Ruttiger L., Habig K., Poths S., Bonin M., Knipper M., Schmidt W.J., et al. Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: in vivo evidence. J Neurosci 27 (2007) 7418-7428. In this study, mice overexpressing nuclear directed ATXN3 developed an enhanced neurological phenotype while mice overexpressing ATXN3 attached to a nuclear export sequence developed a milder phenotype. This study presents in vivo evidence for the requirement of nuclear ATXN3 to cause SCA3.
21. Chou A.H., Yeh T.H., Ouyang P., Chen Y.L., Chen S.Y., and Wang H.L. Polyglutamine-expanded ataxin-3 causes cerebellar dysfunction of SCA3 transgenic mice by inducing transcriptional dysregulation. Neurobiol Dis 31 (2008) 89-101
22. Winborn B.J., Travis S.M., Todi S.V., Scaglione K.M., Xu P., Williams A.J., Cohen R.E., Peng J., and Paulson H.L. The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains. J Biol Chem 283 (2008) 26436-26443. Through the use of in vitro pull-down assays and cell culture studies, the authors of this study demonstrate that ATXN3 is a deubiquitinating enzyme that binds and cleaves mixed linkage ubiquitin chains. The specificity of this activity was regulated by ataxin-3's ubiquitin interacting motifs. ATXN3 is one of the first deubiquitinating enzymes identified that processes complex ubiquitin chains with mixed linkages.
23. Schmitt I., Linden M., Khazneh H., Evert B.O., Breuer P., Klockgether T., and Wuellner U. Inactivation of the mouse Atxn3 (ataxin-3) gene increases protein ubiquitination. Biochem Biophys Res Commun 362 (2007) 734-739. In this paper, the authors generate Atxn3 knockout mice. While these mice do not have an obvious neurological phenotype, an increase in ubiquitinated protein was observed. This study provides in vivo evidence supporting the deubiquitinating function of ataxin-3.
24. Dennis A.P., and O'Malley B.W. Rush hour at the promoter: how the ubiquitin-proteasome pathway polices the traffic flow of nuclear receptor-dependent transcription. J Steroid Biochem Mol Biol 93 (2005) 139-151
25. Kinyamu H.K., Chen J., and Archer T.K. Linking the ubiquitin-proteasome pathway to chromatin remodeling/modification by nuclear receptors. J Mol Endocrinol 34 (2005) 281-297
26. Evert B.O., Araujo J., Vieira-Saecker A.M., de Vos R.A., Harendza S., Klockgether T., and Wullner U. Ataxin-3 represses transcription via chromatin binding, interaction with histone deacetylase 3, and histone deacetylation. J Neurosci 26 (2006) 11474-11486
27. ••].
28. ••] demonstrates that polyglutamine expansion of CACNA1A or Cacna1a does not alter channel function when measured by electrophysiology. These results are in contrast to previous studies done in non-neuronal cells and support the hypothesis that SCA6 is not caused by channel dysfunction.
29. Gatchel J.R., and Zoghbi H.Y. Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet 6 (2005) 743-755
30. Kordasiewicz H.B., Thompson R.M., Clark H.B., and Gomez C.M. C-termini of P/Q-type Ca2+ channel alpha1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity. Hum Mol Genet 15 (2006) 1587-1599. In this study, the authors use an antibody specific to the C-terminus of the CACNA1A protein to demonstrate that this protein is cleaved and that the C-terminal cleavage product is found in the nucleus of cells in vivo. In cell culture, a polyglutamine expansion in the C-terminal fragment was toxic suggesting an alternative hypothesis for SCA6 pathogenesis.
31. van de Leemput J., Chandran J., Knight M.A., Holtzclaw L.A., Scholz S., Cookson M.R., Houlden H., Gwinn-Hardy K., Fung H.C., Lin X., et al. Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS Genet 3 (2007) e108. In this paper the authors identified in-frame deletions in Itpr1 as a cause of movement disorder in mice. Because ITPR1 mapped to a region containing the SCA15 locus, the authors searched for and identified a deletion of ITPR1 in human SCA15 patients.
32. Ikeda Y., Dick K.A., Weatherspoon M.R., Gincel D., Armbrust K.R., Dalton J.C., Stevanin G., Durr A., Zuhlke C., Burk K., et al. Spectrin mutations cause spinocerebellar ataxia type 5. Nat Genet 38 (2006) 184-190
33. Knight M.A., Hernandez D., Diede S.J., Dauwerse H.G., Rafferty I., van de Leemput J., Forrest S.M., Gardner R.J., Storey E., van Ommen G.J., et al. A duplication at chromosome 11q12.2-11q12. 3 is associated with spinocerebellar ataxia type 20. Hum Mol Genet 17 (2008) 3847-3853. Using single nucleotide polymorphism genotyping, the authors identified a chromosomal duplication in an SCA20 family. This is the first copy number variation associated with the ataxias.
34. Waters M.F., Minassian N.A., Stevanin G., Figueroa K.P., Bannister J.P., Nolte D., Mock A.F., Evidente V.G., Fee D.B., Muller U., et al. Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes. Nat Genet 38 (2006) 447-451
35. Shakkottai V.G., Xiao M., Xu L., Wong M., Nerbonne J.M., Ornitz D.M., and Yamada K.A. FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons. Neurobiol Dis 33 (2009) 81-88
36. Trudeau M.M., Dalton J.C., Day J.W., Ranum L.P., and Meisler M.H. Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation. J Med Genet 43 (2006) 527-530
37. Serra H.G., Byam C.E., Lande J.D., Tousey S.K., Zoghbi H.Y., and Orr H.T. Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice. Hum Mol Genet 13 (2004) 2535-2543
38. Houlden H., Johnson J., Gardner-Thorpe C., Lashley T., Hernandez D., Worth P., Singleton A.B., Hilton D.A., Holton J., Revesz T., et al. Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11. Nat Genet 39 (2007) 1434-1436. Tau regulation and deposition play a role in neurodegeneration. The authors of this paper identify tau tubulin kinase 2 as the gene mutated in SCA11. This is the first time a mutation linked to the tau pathway has been identified in spinocerebellar ataxia. It is also the first mutation in a tau kinase implicated in neurodegeneration.
39. Dagda R.K., Merrill R.A., Cribbs J.T., Chen Y., Hell J.W., Usachev Y.M., and Strack S. The Spinocerebellar ataxia 12 gene product and protein phosphatase 2A regulatory subunit B{beta}2 antagonizes neuronal survival by promoting mitochondrial fission. J Biol Chem 283 (2008) 36241-36248
40. Dalski A., Mitulla B., Burk K., Schattenfroh C., Schwinger E., and Zuhlke C. Mutation of the highly conserved cysteine residue 131 of the SCA14 associated PRKCG gene in a family with slow progressive cerebellar ataxia. J Neurol 253 (2006) 1111-1112
41. Verbeek D.S., Goedhart J., Bruinsma L., Sinke R.J., and Reits E.A. PKC gamma mutations in spinocerebellar ataxia type 14 affect C1 domain accessibility and kinase activity leading to aberrant MAPK signaling. J Cell Sci 121 (2008) 2339-2349
42. Zhang Y., Snider A., Willard L., Takemoto D.J., and Lin D. Loss of Purkinje cells in the PKCgamma H101Y transgenic mouse. Biochem Biophys Res Commun 378 (2009) 524-528
43. Nonis D., Schmidt M.H., van de Loo S., Eich F., Dikic I., Nowock J., and Auburger G. Ataxin-2 associates with the endocytosis complex and affects EGF receptor trafficking. Cell Signal 20 (2008) 1725-1739
44. Moseley M.L., Zu T., Ikeda Y., Gao W., Mosemiller A.K., Daughters R.S., Chen G., Weatherspoon M.R., Clark H.B., Ebner T.J., et al. Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nat Genet 38 (2006) 758-769
45. Lim J., Hao T., Shaw C., Patel A.J., Szabo G., Rual J.F., Fisk C.J., Li N., Smolyar A., Hill D.E., et al. A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 125 (2006) 801-814
46. Wakamiya M., Matsuura T., Liu Y., Schuster G.C., Gao R., Xu W., Sarkar P.S., Lin X., and Ashizawa T. The role of ataxin 10 in the pathogenesis of spinocerebellar ataxia type 10. Neurology 67 (2006) 607-613
47. Ishikawa K., Toru S., Tsunemi T., Li M., Kobayashi K., Yokota T., Amino T., Owada K., Fujigasaki H., Sakamoto M., et al. An autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 is associated with a single-nucleotide substitution in the 5′ untranslated region of the gene encoding a protein with spectrin repeat and Rho guanine-nucleotide exchange-factor domains. Am J Hum Genet 77 (2005) 280-296