Spinocerebellar Ataxia Type 1: Molecular Mechanisms of Neurodegeneration and Preclinical Studies

Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1049)

Abstract

Spinocerebellar ataxia type 1 (SCA1) is an adult-onset, inherited disease that leads to degeneration of Purkinje cells of the cerebellum and culminates in death 10–30 years after disease onset. SCA1 is caused by a CAG repeat mutation in the ATXN1 gene, encoding the ATXN1 protein with an abnormally expanded polyglutamine tract. As neurodegeneration progresses, other brain regions become involved and contribute to cognitive deficits as well as problems with speech, swallowing, and control of breathing. The fundamental basis of pathology is an aberration in the normal function of Purkinje cells affecting regulation of gene transcription and RNA splicing. Glutamine-expanded ATXN1 is highly stable and more resistant to degradation. Moreover, phosphorylation at S776 in ATXN1 is a post-translational modification known to influence protein levels. SCA1 remains an untreatable disease managed only by palliative care. Preclinical studies are founded on the principle that mutant protein load is toxic and attenuating ATXN1 protein levels can alleviate disease. Two approaches being pursued are targeting gene expression or protein levels. Viral delivery of miRNAs harnesses the RNAi pathway to destroy ATXN1 mRNA. This approach shows promise in mouse models of disease. At the protein level, kinase inhibitors that block ATXN1-S776 phosphorylation may lead to therapeutic clearance of unphosphorylated ATXN1.

Keywords

Neurodegeneration Polyglutamine Therapeutic approaches 

References

  1. 1.
    Banfi S et al (1993) Mapping and cloning of the critical region for the spinocerebellar ataxia Type 1 gene (SCA1) in a yeast artificial chromosome contig spanning 1.2 Mb. Genomics 18(3):627–635CrossRefGoogle Scholar
  2. 2.
    Orr HT et al (1993) Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 4(3):221–226CrossRefGoogle Scholar
  3. 3.
    Chung MY et al (1993) Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I. Nat Genet 5(3):254–258CrossRefGoogle Scholar
  4. 4.
    Klement IA et al (1998) Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 95(1):41–53CrossRefGoogle Scholar
  5. 5.
    Kim E, Lu HC, Zoghbi HY (2013) Structural basis of protein complex formation and reconfiguration by polyglutamine disease protein ataxin-1 and capicua. Genes Dev 27(6):590–595CrossRefGoogle Scholar
  6. 6.
    Lam YC et al (2006) ATAXIN-1 interacts with the repressor capicua in Its native complex to cause SCA1 neuropathology. Cell 127(7):1335–1347CrossRefGoogle Scholar
  7. 7.
    Watase K et al (2002) A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron 34(6):905–919CrossRefGoogle Scholar
  8. 8.
    Duvick Lisa et al (2010) SCA1-like disease in mice expressing wild-type ataxin-1 with a serine to aspartic acid replacement at residue 776. Neuron 67(6):929–935CrossRefGoogle Scholar
  9. 9.
    Emamian ES et al (2003) Serine 776 of Ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice. Neuron 38(3):375–387CrossRefGoogle Scholar
  10. 10.
    Fernandez-Funez P et al (2000) Identification of genes that modify Ataxin-1-induced neurodegeneration. Nature 408(6808):101–106CrossRefGoogle Scholar
  11. 11.
    Gennarino VA et al (2015) Pumilio1 haploinsufficiency leads to SCA1-like neurodegeneration by increasing wild-type Ataxin1 levels. Cell 160(6):1087–1098CrossRefGoogle Scholar
  12. 12.
    Jorgensen ND et al (2009) Phosphorylation of ATXN1 at Ser776 in the cerebellum. J Neurochem 110(2):675–686CrossRefGoogle Scholar
  13. 13.
    Chen HK et al (2003) Interaction of Akt-phosphorylated Ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113(4):457–468CrossRefGoogle Scholar
  14. 14.
    Jafar-nejad P, Ward CS, Richman R, Orr HT, Zoghbi HY (2011) Regional rescue of spinocerebellar ataxia type 1 phenotypes by 14-3-3 ε haploinsufficiency in mice underscores complex pathogenicity in neurodegeneration. PNAS 108(5):2142–2147CrossRefGoogle Scholar
  15. 15.
    Lai S, O’Callaghan B, Zoghbi HY, Orr HT (2011) 14-3-3 binding to ataxin-1 (ATXN1) regulates its dephosphorylation at Ser-776 and transport to the nucleus. J Biol Chem 286(40):34606–34616CrossRefGoogle Scholar
  16. 16.
    Lim J et al (2008) Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 452(7188):713–718CrossRefGoogle Scholar
  17. 17.
    Masuda A, Takeda JI, Ohno K (2016) FUS-mediated regulation of alternative RNA processing in neurons: insights from global transcriptome analysis. Wiley Interdiscip Rev RNA 2–5Google Scholar
  18. 18.
    Sánchez-hernández N et al (2016) The in vivo dynamics of TCERG1, a factor that couples transcriptional elongation with splicing. RNA 22(4):571–582CrossRefGoogle Scholar
  19. 19.
    Lin X, Antalffy B, Kang D, Orr HT, Zoghbi HY (2000) Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat Neurosci 3(2):157–163CrossRefGoogle Scholar
  20. 20.
    Serra HG et al (2004) Gene profiling links SCA1 pathophysiology to glutamate signaling in purkinje cells of transgenic mice. Hum Mol Genet 13(20):2535–2543CrossRefGoogle Scholar
  21. 21.
    Zu Tao et al (2004) Recovery from polyglutamine-induced neurodegeneration in conditional SCA1 transgenic mice. J Neurosci Off J Soc Neurosci 24(40):8853–8861CrossRefGoogle Scholar
  22. 22.
    Hearst SM, Lopez ME, Shao Q, Liu Y, Vig PJS (2010) Dopamine D2 receptor signaling modulates mutant ataxin-1 S776 phosphorylation and aggregation. J Neurochem 114(3):706–716CrossRefGoogle Scholar
  23. 23.
    Cvetanovic M, Patel JM, Marti HH, K AR, Opal P (2011) Vascular endothelial growth factor ameliorates the ataxic phenotype in a mouse model of spinocerebellar ataxia type 1. Nat Med 17(11):1445–1447CrossRefGoogle Scholar
  24. 24.
    Ruegsegger C et al (2016) Impaired mTORC1-dependent expression of homer-3 influences SCA1 pathophysiology. Neuron 89(1):129–146CrossRefGoogle Scholar
  25. 25.
    Serra HG et al (2006) RORa-mediated purkinje cell development determines disease severity in adult SCA1 mice. Cell 127(4):697–708CrossRefGoogle Scholar
  26. 26.
    Ebner BA et al (2013) Purkinje cell ataxin-1 modulates climbing fiber synaptic input in developing and adult mouse cerebellum. J Neurosci 33(13):5806–5820CrossRefGoogle Scholar
  27. 27.
    Ingram M, et al (2016) Cerebellar transcriptome profiles of ATXN1 transgenic mice reveal SCA1 disease progression and protection pathways. Neuron 1194–1207CrossRefGoogle Scholar
  28. 28.
    Acker T, Beck H, Plate KH (2001) Cell type specific expression of vascular endothelial growth factor and Angiopoietin-1 and -2 suggests an important role of astrocytes in cerebellar vascularization. Mech Dev 108(1–2):45–57CrossRefGoogle Scholar
  29. 29.
    de Almodovar CR et al (2010) Matrix-binding vascular endothelial growth factor (VEGF) isoforms guide granule cell migration in the cerebellum via VEGF receptor Flk1. J Neurosci 30(45):15052–15066CrossRefGoogle Scholar
  30. 30.
    Barnes JA et al (2011) Abnormalities in the climbing fiber-purkinje cell circuitry contribute to neuronal dysfunction in ATXN1[82Q] mice. J Neurosci Off J Soc Neurosci 31(36):12778–12789CrossRefGoogle Scholar
  31. 31.
    Park J et al (2013) RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1. Nature 498(7454):325–331CrossRefGoogle Scholar
  32. 32.
    Xia H et al (2004) RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med 10(8):816–820CrossRefGoogle Scholar
  33. 33.
    Boudreau RL, Martins I, Davidson BL (2009) Artificial microRNAs as siRNA shuttles: improved safety as compared to shRNAs in Vitro and in Vivo. Mol Ther J Am Soc Gene Ther 17(1):169–175CrossRefGoogle Scholar
  34. 34.
    McBride JL et al (2008) Artificial miRNAs Mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi. Proc Natl Acad Sci USA 105(15):5868–5873CrossRefGoogle Scholar
  35. 35.
    Keiser MS, Geoghegan JC, Boudreau RL, Lennox KA, Davidson BL (2013) RNAi or overexpression: alternative therapies for spinocerebellar ataxia type 1. Neurobiol Dis 56C:6–13CrossRefGoogle Scholar
  36. 36.
    Keiser MS, Boudreau RL, Davidson BL (2014) Broad therapeutic benefit after RNAi expression vector delivery to deep cerebellar nuclei: implications for spinocerebellar ataxia type 1 therapy. Mol Ther 2:588–595CrossRefGoogle Scholar
  37. 37.
    Kordasiewicz HB et al (2012) Sustained therapeutic reversal of huntington’s disease by transient repression of huntingtin synthesis. Neuron 74(6):1031–1044CrossRefGoogle Scholar
  38. 38.
    Miller TM et al (2013) An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol 12(5):435–442CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institute for Translational Neuroscience, University of MinnesotaMinneapolisUSA
  2. 2.Medical Scientist Training ProgramUniversity of MinnesotaMinneapolisUSA
  3. 3.Graduate Program in NeuroscienceUniversity of MinnesotaMinneapolisUSA
  4. 4.Department of Laboratory Medicine and PathologyUniversity of MinnesotaMinneapolisUSA

Personalised recommendations