Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide repeat expansion in ATXN1 that leads to an abnormally long polyglutamine tract in the subsequent protein, ataxin-1 (ATXN1). Mutant ATXN1 has a propensity to misfold, resist cellular degradation, and increase in toxicity as its levels rise. This toxicity occurs by a gain of function mechanism with evidence point to transcriptional derangements as an early, presymptomatic pathogenic event. We recently discovered that the earliest abnormalities in Purkinje cells (cells that are most vulnerable in SCA1) are not caused by cell- autonomous changes but in a non-cell autonomous manner by affecting the proliferation and fate of cerebellar post-natal stem cells. In this proposal, we will test the hypothesis that the underlying SCA1 pathology has its roots in early developmental processes and that if these defects are overcome one might be able to delay or ameliorate later neurodegeneration, thus paving the way for therapy for this currently untreatable condition.

Public Health Relevance

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide repeat expansion in ATXN1, thus leading to a misfolded, degradation resistant, toxic mutant protein. We discovered that early cerebellar developmental abnormalities in SCA1 occur in a non-autonomous manner. In this proposal we seek to elucidate the consequences of these early developmental changes and whether thwarting these abnormalities can ameliorate disease progression. Ultimately helping us to understand the pathological basis of SCA1 and identifying possible therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS082351-07
Application #
9933085
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Miller, Daniel L
Project Start
2013-05-15
Project End
2024-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Neurology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Cvetanovic, Marija; Hu, Yuan-Shih; Opal, Puneet (2017) Mutant Ataxin-1 Inhibits Neural Progenitor Cell Proliferation in SCA1. Cerebellum 16:340-347
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Lin, Ni-Hsuan; Huang, Yu-Shan; Opal, Puneet et al. (2016) The role of gigaxonin in the degradation of the glial-specific intermediate filament protein GFAP. Mol Biol Cell 27:3980-3990
Didonna, Alessandro; Opal, Puneet (2016) Advances in Sequencing Technologies for Understanding Hereditary Ataxias: A Review. JAMA Neurol 73:1485-1490
Rozenfeld, Michael N; Nemeth, Alexander J; Walker, Matthew T et al. (2015) An investigation of diffusion imaging techniques in the evaluation of spinocerebellar ataxia and multisystem atrophy. J Clin Neurosci 22:166-72
Didonna, Alessandro; Opal, Puneet (2015) The promise and perils of HDAC inhibitors in neurodegeneration. Ann Clin Transl Neurol 2:79-101
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Venkatraman, Anand; Hu, Yuan-Shih; Didonna, Alessandro et al. (2014) The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1. Hum Mol Genet 23:3733-45

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