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

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Polyglutamine Disorders

Part of the book series: Advances in Experimental Medicine and Biology ((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.

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Author information

Authors and Affiliations

  1. Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA

    Judit M. Pérez Ortiz & Harry T. Orr

  2. Medical Scientist Training Program, University of Minnesota, Minneapolis, MN, 55455, USA

    Judit M. Pérez Ortiz

  3. Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA

    Judit M. Pérez Ortiz

  4. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA

    Harry T. Orr

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  1. Judit M. Pérez Ortiz
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  2. Harry T. Orr
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Correspondence to Harry T. Orr .

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Editors and Affiliations

  1. Department of Biomedical Sciences and Medicine; Centre for Biomedical Research and Algarve Biomedical Center, University of Algarve, Faro, Portugal

    Clévio Nóbrega

  2. Center for Neuroscience and Cell Biology and Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

    Luís Pereira de Almeida

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Pérez Ortiz, J.M., Orr, H.T. (2018). Spinocerebellar Ataxia Type 1: Molecular Mechanisms of Neurodegeneration and Preclinical Studies. In: Nóbrega, C., Pereira de Almeida, L. (eds) Polyglutamine Disorders. Advances in Experimental Medicine and Biology, vol 1049. Springer, Cham. https://doi.org/10.1007/978-3-319-71779-1_6

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