title: SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity.
abstract: We targeted 266 CAG repeats (a number that causes infantile-onset disease) into the mouse Sca7 locus to generate an authentic model of spinocerebellar ataxia type 7 (SCA7). These mice reproduced features of infantile SCA7 (ataxia, visual impairments, and premature death) and showed impaired short-term synaptic potentiation; downregulation of photoreceptor-specific genes, despite apparently normal CRX activity, led to shortening of photoreceptor outer segments. Wild-type ataxin-7 was barely detectable, as was mutant ataxin-7 in young animals; with increasing age, however, ataxin-7 staining became more pronounced. Neurons that appeared most vulnerable had relatively high levels of mutant ataxin-7; it is interesting, however, that marked dysfunction occurred in these neurons weeks prior to the appearance of nuclear inclusions. These data demonstrate that glutamine expansion stabilizes mutant ataxin-7, provide an explanation for selective neuronal vulnerability, and show that mutant ataxin-7 impairs posttetanic potentiation (PTP).
authors.affiliation: Division of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Seung Yun
authors.initials: SY
authors.lastname: Yoo
authors.forename: Mark E
authors.initials: ME
authors.lastname: Pennesi
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Weeber
authors.forename: Bisong
authors.initials: B
authors.lastname: Xu
authors.forename: Richard
authors.initials: R
authors.lastname: Atkinson
authors.forename: Shiming
authors.initials: S
authors.lastname: Chen
authors.forename: Dawna L
authors.initials: DL
authors.lastname: Armstrong
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Wu
authors.forename: J David
authors.initials: JD
authors.lastname: Sweatt
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
mesh_terms: D000818:Animals; D000067719:Ataxin-7; D002531:Cerebellum / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006624:Hippocampus / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D017774:Long-Term Potentiation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009473:Neuronal Plasticity; D009474:Neurons / Q000473:pathology* / Q000502:physiology; D010641:Phenotype; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology / Q000503:physiopathology; D017948:Retinal Rod Photoreceptor Cells / Q000473:pathology / Q000503:physiopathology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D012995:Solubility; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D015534:Trans-Activators / Q000378:metabolism
chemical_list: C000593829:ATXN7 protein, human; D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D015534:Trans-Activators; C109288:cone rod homeobox protein