Author:
Duvick Lisa,Southern W. Michael,Benzow Kellie,Burch Zoe N.,Handler Hillary P.,Mitchell Jason S.,Kuivinen Hannah,Gadiparthi Udaya Keerthy,Yang Praseuth,Soles Alyssa,Scheeler Carrie,Rainwater Orion,Serres Shannah,Lind Erin,Nichols-Meade Tessa,O’Callaghan Brennon,Zoghbi Huda Y.,Cvetanovic Marija,Wheeler Vanessa C.,Ervasti James M.,Koob Michael D.,Orr Harry T.
Abstract
ABSTRACTSpinocerebellar 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 mouseAtxn1coding exons replaced by human exons encoding 146 glutamines.F-ATXN1146Q/2Qmice manifest SCA1-like phenotypes including motor and cognitive deficits, wasting, and decreased survival. CNS contributions to disease were revealed usingATXN1146Q/2Q;Nestin-Cremice, that showed improved rotarod, open field and Barnes maze performances. Striatal contributions to motor deficits were examined usingf-ATXN1146Q/2Q;Rgs9-Cremice. Mice lacking striatalATXN1146Q/2Qhad improved rotarod performance late in disease. Muscle contributions to disease were revealed inf-ATXN1146Q/2Q;ACTA1-Cremice which lacked muscle pathology and kyphosis seen inf-ATXN1146Q/2Qmice. Kyphosis was not improved inf-ATXN1146Q/2Q;Nestin-Cremice. Thus, optimal SCA1 therapeutics will require targeting mutant ATXN1 toxic actions in multiple brain regions and muscle.
Publisher
Cold Spring Harbor Laboratory