SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity.
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).
Yoo
Seung Yun
SY
Division of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
Pennesi
Mark E
ME
Weeber
Edwin J
EJ
Xu
Bisong
B
Atkinson
Richard
R
Chen
Shiming
S
Armstrong
Dawna L
DL
Wu
Samuel M
SM
Sweatt
J David
JD
Zoghbi
Huda Y
HY
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
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