Regional vulnerability in a neurodegenerative disease: Delineating SCA1 CNS and muscle therapeutic targets using a conditional mutant ATXN1 mouse

Duvick, L.; Southern, W. M.; Benzow, K.; Handler, H. P.; Mitchell, J. S.; Kuivinen, H.; Gadiparthi, U. K.; Yang, P.; Soles, A.; Scheeler, C.; Rainwater, O.; Serres, S.; Larson, E.; Nichols-Meade, T.; You, Y.; Zoghbi, H. Y.; Ervasti, J. M.; Cvetanovic, M.; Koob, M. D.; Orr, H. T.

doi:10.1101/2023.02.08.527710

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bioRxiv · 10.1101/2023.02.08.527710

Regional vulnerability in a neurodegenerative disease: Delineating SCA1 CNS and muscle therapeutic targets using a conditional mutant ATXN1 mouse

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Abstract

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the widely expressed ATXN1 protein. To elucidate anatomical regions and cell types that underlie mutant ATXN1-induced disease phenotypes, we developed a floxed conditional knockout mouse model (f-ATXN1146Q/2Q) having mouse Atxn1 coding exons replaced by human exons encoding 146 glutamines. F-ATXN1146Q/2Q mice manifest SCA1-like phenotypes including motor and cognitive deficits, wasting, and decreased survival. CNS contributions to disease were revealed using ATXN1146Q/2Q;Nestin-Cre mice, that showed improved rotarod, open field and Barnes maze performances. Striatal contributions to motor deficits were examined using f-ATXN1146Q/2Q;Rgs9-Cre mice. Mice lacking striatal ATXN1146Q/2Q had improved rotarod performance late in disease. Muscle contributions to disease were revealed in f-ATXN1146Q/2Q;ACTA1-Cre mice which lacked muscle pathology and kyphosis seen in f-ATXN1146Q/2Q mice. Kyphosis was not improved in f-ATXN1146Q/2Q;Nestin-Cre mice. Thus, optimal SCA1 therapeutics will require targeting mutant ATXN1 toxic actions in multiple brain regions and muscle.

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Duvick, L., Southern, W. M., Benzow, K., Handler, H. P., Mitchell, J. S., Kuivinen, H., Gadiparthi, U. K., Yang, P., Soles, A., Scheeler, C., Rainwater, O., Serres, S., Larson, E., Nichols-Meade, T., You, Y., Zoghbi, H. Y., Ervasti, J. M., Cvetanovic, M., Koob, M. D., Orr, H. T.. 2023-02-08. Regional vulnerability in a neurodegenerative disease: Delineating SCA1 CNS and muscle therapeutic targets using a conditional mutant ATXN1 mouse. https://doi.org/10.1101/2023.02.08.527710

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