Mapping SCA1 regional vulnerabilities reveals neural and skeletal muscle contributions to disease

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the widely expressed ataxin-1 (ATXN1) protein. To elucidate anatomical regions and cell types that underlie mutant ATXN1-induced disease phenotypes, we developed a floxed conditiona...

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Bibliographic Details
Published in:JCI insight 2024-05, Vol.9 (9)
Main Authors: Duvick, Lisa, Southern, W Michael, Benzow, Kellie A, Burch, Zoe N, Handler, Hillary P, Mitchell, Jason S, Kuivinen, Hannah, Gadiparthi, Udaya, Yang, Praseuth, Soles, Alyssa, Sheeler, Carrie A, Rainwater, Orion, Serres, Shannah, Lind, Erin B, Nichols-Meade, Tessa, You, Yun, O'Callaghan, Brennon, Zoghbi, Huda Y, Cvetanovic, Marija, Wheeler, Vanessa C, Ervasti, James M, Koob, Michael D, Orr, Harry T
Format: Article
Language:English
Subjects:
Animals
Ataxin-1 - genetics
Ataxin-1 - metabolism
Disease Models, Animal
Female
Gene Knock-In Techniques
Humans
Male
Mice
Mice, Transgenic
Muscle, Skeletal - metabolism
Muscle, Skeletal - pathology
Neurons - metabolism
Neurons - pathology
Phenotype
Spinocerebellar Ataxias - genetics
Spinocerebellar Ataxias - pathology
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Summary:Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the widely expressed ataxin-1 (ATXN1) protein. To elucidate anatomical regions and cell types that underlie mutant ATXN1-induced disease phenotypes, we developed a floxed conditional knockin mouse (f-ATXN1146Q/2Q) with mouse Atxn1 coding exons replaced by human ATXN1 exons encoding 146 glutamines. f-ATXN1146Q/2Q mice manifested SCA1-like phenotypes including motor and cognitive deficits, wasting, and decreased survival. Central nervous system (CNS) contributions to disease were revealed using f-ATXN1146Q/2Q;Nestin-Cre mice, which showed improved rotarod, open field, and Barnes maze performance by 6-12 weeks of age. In contrast, striatal contributions to motor deficits using f-ATXN1146Q/2Q;Rgs9-Cre mice revealed that mice lacking ATXN1146Q/2Q in striatal medium-spiny neurons showed a trending improvement in rotarod performance at 30 weeks of age. Surprisingly, a prominent role for muscle contributions to disease was revealed in f-ATXN1146Q/2Q;ACTA1-Cre mice based on their recovery from kyphosis and absence of muscle pathology. Collectively, data from the targeted conditional deletion of the expanded allele demonstrated CNS and peripheral contributions to disease and highlighted the need to consider muscle in addition to the brain for optimal SCA1 therapeutics.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.176057