Spinocerebellar ataxia type 1

Molecular mechanisms of neurodegeneration and preclinical studies

Judit M. Pérez Ortiz, Harry T Orr

Research output: Chapter in Book/Report/Conference proceedingChapter

3 Citations (Scopus)

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.

Original languageEnglish (US)
Title of host publicationAdvances in Experimental Medicine and Biology
PublisherSpringer New York LLC
Pages135-145
Number of pages11
DOIs
StatePublished - Jan 1 2018

Publication series

NameAdvances in Experimental Medicine and Biology
Volume1049
ISSN (Print)0065-2598
ISSN (Electronic)2214-8019

Fingerprint

Spinocerebellar Ataxias
Phosphorylation
Purkinje Cells
Proteins
RNA Splicing
Gene encoding
Poisons
Pathology
Mutant Proteins
Transcription
Post Translational Protein Processing
Deglutition
RNA Interference
Glutamine
Aberrations
MicroRNAs
Palliative Care
Gene expression
Cerebellum
Genes

Keywords

  • Neurodegeneration
  • Polyglutamine
  • Therapeutic approaches

PubMed: MeSH publication types

  • Journal Article
  • Review

Cite this

Pérez Ortiz, J. M., & Orr, H. T. (2018). Spinocerebellar ataxia type 1: Molecular mechanisms of neurodegeneration and preclinical studies. In Advances in Experimental Medicine and Biology (pp. 135-145). (Advances in Experimental Medicine and Biology; Vol. 1049). Springer New York LLC. https://doi.org/10.1007/978-3-319-71779-1_6

Spinocerebellar ataxia type 1 : Molecular mechanisms of neurodegeneration and preclinical studies. / Pérez Ortiz, Judit M.; Orr, Harry T.

Advances in Experimental Medicine and Biology. Springer New York LLC, 2018. p. 135-145 (Advances in Experimental Medicine and Biology; Vol. 1049).

Research output: Chapter in Book/Report/Conference proceedingChapter

Pérez Ortiz, JM & Orr, HT 2018, Spinocerebellar ataxia type 1: Molecular mechanisms of neurodegeneration and preclinical studies. in Advances in Experimental Medicine and Biology. Advances in Experimental Medicine and Biology, vol. 1049, Springer New York LLC, pp. 135-145. https://doi.org/10.1007/978-3-319-71779-1_6
Pérez Ortiz JM, Orr HT. Spinocerebellar ataxia type 1: Molecular mechanisms of neurodegeneration and preclinical studies. In Advances in Experimental Medicine and Biology. Springer New York LLC. 2018. p. 135-145. (Advances in Experimental Medicine and Biology). https://doi.org/10.1007/978-3-319-71779-1_6
Pérez Ortiz, Judit M. ; Orr, Harry T. / Spinocerebellar ataxia type 1 : Molecular mechanisms of neurodegeneration and preclinical studies. Advances in Experimental Medicine and Biology. Springer New York LLC, 2018. pp. 135-145 (Advances in Experimental Medicine and Biology).
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