Pathogenic mechanisms underlying spinocerebellar ataxia type 1
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Cellular and Molecular Life Sciences
REVIEW
Pathogenic mechanisms underlying spinocerebellar ataxia type 1 Leon Tejwani1,2 · Janghoo Lim1,2,3,4,5 Received: 6 November 2019 / Revised: 6 March 2020 / Accepted: 6 April 2020 © Springer Nature Switzerland AG 2020
Abstract The family of hereditary cerebellar ataxias is a large group of disorders with heterogenous clinical manifestations and genetic etiologies. Among these, over 30 autosomal dominantly inherited subtypes have been identified, collectively referred to as the spinocerebellar ataxias (SCAs). Generally, the SCAs are characterized by a progressive gait impairment with classical cerebellar features, and in a subset of SCAs, accompanied by extra-cerebellar features. Beyond the common gait impairment and cerebellar atrophy, the wide range of additional clinical features observed across the SCAs is likely explained by the diverse set of mutated genes that encode proteins with seemingly disparate functional roles in nervous system biology. By synthesizing knowledge obtained from studies of the various SCAs over the past several decades, convergence onto a few key cellular changes, namely ion channel dysfunction and transcriptional dysregulation, has become apparent and may represent central mechanisms of cerebellar disease pathogenesis. This review will detail our current understanding of the molecular pathogenesis of the SCAs, focusing primarily on the first described autosomal dominant spinocerebellar ataxia, SCA1, as well as the emerging common core mechanisms across the various SCAs. Keywords Spinocerebellar ataxia · CAG/polyglutamine disorder · Repeat expansion · SCA1 · ATXN1 · Ataxin-1 · Neurodegeneration
Introduction Ataxia is a broadly defined clinical feature of many neurological disorders and is characterized by an impairment in the coordination of voluntary movements, including those associated with speech, gait, and fine motor movements, among others. Ataxia can manifest due to a variety of environmental or genetic reasons. There have been
* Janghoo Lim [email protected] 1
Interdepartmental Neuroscience Program, Yale School of Medicine, 295 Congress Avenue, New Haven, CT 06510, USA
2
Department of Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
3
Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA
4
Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale School of Medicine, New Haven, CT 06510, USA
5
Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06510, USA
several groups of monogenic inherited ataxias that have been described, which have been collectively termed as the hereditary cerebellar ataxias. Broadly, the hereditary cerebellar ataxias are a heterogenous family of disorders that result primarily in a progressive degeneration of the tissues involved in the coordination of movement, some of which progress to affect bulbar regions involved in respiratory functions. Although each individual hereditary ataxia is considered a rare disease, the family of h
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