title: A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration.
abstract: To faithfully recreate the features of the human neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) in the mouse, we targeted 154 CAG repeats into the endogenous mouse locus. Sca1(154Q/2Q) mice developed a progressive neurological disorder that resembles human SCA1, featuring motor incoordination, cognitive deficits, wasting, and premature death, accompanied by Purkinje cell loss and age-related hippocampal synaptic dysfunction. Mutant ataxin-1 solubility varied with brain region, being most soluble in the neurons most vulnerable to degeneration. Solubility decreased overall as the mice aged; Purkinje cells, the most affected in SCA1, did not form aggregates of mutant protein until an advanced stage of disease. It appears that those neurons that cannot sequester the mutant protein efficiently and thereby curb its toxicity suffer the worst damage from polyglutamine-induced toxicity.
authors.affiliation: Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Kei
authors.initials: K
authors.lastname: Watase
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Weeber
authors.forename: Bisong
authors.initials: B
authors.lastname: Xu
authors.forename: Barbara
authors.initials: B
authors.lastname: Antalffy
authors.forename: Lisa
authors.initials: L
authors.lastname: Yuva-Paylor
authors.forename: Kouichi
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kano
authors.forename: Richard
authors.initials: R
authors.lastname: Atkinson
authors.forename: Yaling
authors.initials: Y
authors.lastname: Sun
authors.forename: Dawna L
authors.initials: DL
authors.lastname: Armstrong
authors.forename: J David
authors.initials: JD
authors.lastname: Sweatt
authors.forename: Harry T
authors.initials: HT
authors.lastname: Orr
authors.forename: Richard
authors.initials: R
authors.lastname: Paylor
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
mesh_terms: D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D012995:Solubility; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D018911:Trinucleotide Repeats / Q000235:genetics*
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins