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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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1172/jci.insight.176057 |
| format | Article |
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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. 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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.</description><subject>Animals</subject><subject>Ataxin-1 - genetics</subject><subject>Ataxin-1 - metabolism</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Gene Knock-In Techniques</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Muscle, Skeletal - metabolism</subject><subject>Muscle, Skeletal - pathology</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>Phenotype</subject><subject>Spinocerebellar Ataxias - genetics</subject><subject>Spinocerebellar Ataxias - pathology</subject><issn>2379-3708</issn><issn>2379-3708</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkEtLAzEUhYMottT-ARcySzeteUwmmWUpvqDiQl2HJHOnps7LJFPw3xtpFVf3ce45XD6ELgleEiLozc66peuC277HJREF5uIETSkT5YIJLE__9RM0D2GHMSYip5jLczRhkhOas3yK9JMeBtdts5f1imQetq7vdJPtx6YDr41rXHQQkrAH3YSsg9EnWXdVFj6ggZiGdgy2gcz2XfTOjDElhCz2WeUC6AAX6KxOVpgf6wy93d2-rh8Wm-f7x_Vqs7C0lHEhOKmYZJphbkRR0rq2YGsrwVBqTElwej4nnNe8LAWlBQacFjUXksvK2IrN0PUhd_D95wghqtYFC02jO-jHoGgpcowLlufplB5Ore9D8FCrwbtW-y9FsPqhqxJddaSrDnST6eqYP5oWqj_LL0v2DVnseUs</recordid><startdate>20240508</startdate><enddate>20240508</enddate><creator>Duvick, Lisa</creator><creator>Southern, W Michael</creator><creator>Benzow, Kellie A</creator><creator>Burch, Zoe N</creator><creator>Handler, Hillary P</creator><creator>Mitchell, Jason S</creator><creator>Kuivinen, Hannah</creator><creator>Gadiparthi, Udaya</creator><creator>Yang, Praseuth</creator><creator>Soles, Alyssa</creator><creator>Sheeler, Carrie A</creator><creator>Rainwater, Orion</creator><creator>Serres, Shannah</creator><creator>Lind, Erin B</creator><creator>Nichols-Meade, Tessa</creator><creator>You, Yun</creator><creator>O'Callaghan, Brennon</creator><creator>Zoghbi, Huda Y</creator><creator>Cvetanovic, Marija</creator><creator>Wheeler, Vanessa C</creator><creator>Ervasti, James M</creator><creator>Koob, Michael D</creator><creator>Orr, Harry T</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-0700-3349</orcidid><orcidid>https://orcid.org/0000-0002-0292-7614</orcidid><orcidid>https://orcid.org/0000-0001-6118-741X</orcidid></search><sort><creationdate>20240508</creationdate><title>Mapping SCA1 regional vulnerabilities reveals neural and skeletal muscle contributions to disease</title><author>Duvick, Lisa ; 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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.</abstract><cop>United States</cop><pmid>38512434</pmid><doi>10.1172/jci.insight.176057</doi><orcidid>https://orcid.org/0000-0002-0700-3349</orcidid><orcidid>https://orcid.org/0000-0002-0292-7614</orcidid><orcidid>https://orcid.org/0000-0001-6118-741X</orcidid><oa>free_for_read</oa></addata></record> |
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| 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 |
| title | Mapping SCA1 regional vulnerabilities reveals neural and skeletal muscle contributions to disease |
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