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Spinocerebellar Ataxia Type 7: From Mechanistic Pathways to Therapeutic Opportunities

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Trials for Cerebellar Ataxias

Part of the book series: Contemporary Clinical Neuroscience ((CCNE))

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Abstract

Spinocerebellar ataxia type 7 (SCA7) is a cerebellar and retinal neurodegenerative disease caused by a CAG/polyglutamine (polyQ) expansion mutation in the ataxin-7 (ATXN7) gene. PolyQ-expanded ataxin-7 protein interferes with the histone modification activity of the STAGA co-activator complex and consequently alters the expression of STAGA-regulated genes. In the SCA7 pathogenic cascade, epigenetic dysregulation of the DNA repair interactome, combined with increased oxidative stress, leads to the accumulation of DNA damage and PARP1-mediated depletion of nicotinamide adenine dinucleotide (NAD+) levels. Subsequent breakdown of the SIRT1/NAD+—PPARγ/PGC-1α transcriptional regulatory axis, arising from NAD+ depletion, results in altered expression of calcium homeostasis genes, culminating in neuronal dysfunction and death. Here, we describe the current mechanistic understanding of SCA7, highlighting recent advances in this field. Based upon our understanding of the cellular and molecular basis of SCA7 disease pathogenesis, we delineate both known and prospective therapeutic targets and treatment strategies that could ameliorate polyQ-expanded ataxin-7 neurotoxicity, including recent progress toward an antisense oligonucleotide therapy directed against ATXN7 mRNA. In the near future, preclinical and clinical exploration of these therapeutic opportunities may yield a highly effective treatment for SCA7.

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Authors and Affiliations

  1. Department of Medical Biotechnology, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland

    Pawel M. Switonski

  2. Departments of Pathology & Laboratory Medicine, Neurology, and Biological Chemistry, UCI Institute for Neurotherapeutics, University of California, Irvine, Irvine, CA, USA

    Albert R. La Spada

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Correspondence to Albert R. La Spada .

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  1. Professor of Neurology, Shuang Ho Hospital, Taipei Medical University, Taipei, (Republic of China), Taiwan

    Bing-wen Soong

  2. Professor of Neuroanatomy, University of Mons and CHU-Charleroi, Charleroi, Belgium

    Mario Manto

  3. Paris Brain Institute, (Institut du Cerveau – ICM), CNRS INSERM, Sorbonne Université, APHP, Paris, France

    Alexis Brice

  4. Department of Neurology, Spencer Fox Eccles School of Medicine University of Utah, Salt Lake City, UT, USA

    Stefan M. Pulst

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Switonski, P.M., La Spada, A.R. (2023). Spinocerebellar Ataxia Type 7: From Mechanistic Pathways to Therapeutic Opportunities. In: Soong, Bw., Manto, M., Brice, A., Pulst, S.M. (eds) Trials for Cerebellar Ataxias. Contemporary Clinical Neuroscience. Springer, Cham. https://doi.org/10.1007/978-3-031-24345-5_17

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