title: Polyglutamine-expanded ataxin-7 causes cerebellar dysfunction by inducing transcriptional dysregulation.
abstract: In the present study, we prepared an animal model of adult-onset spinocerebellar ataxia type 7 (SCA7) by generating transgenic mice expressing polyglutamine-expanded ataxin-7-Q52. Mutant ataxin-7-Q52 was expressed in brain areas implicated in SCA7 neurodegeneration, including cerebellum and inferior olivary nucleus. Ataxin-7-Q52 transgenic mice exhibited symptoms of motor dysfunction with an onset age of 7 months, and neurological phenotypes deteriorated in the following months. Ten to eleven-month-old ataxin-7-Q52 mice displayed ataxic symptoms without prominent cerebellar neuronal death, suggesting that ataxin-7-Q52 causes cerebellar malfunction and ataxia. To investigate the involvement of transcriptional dysregulation in ataxin-7-Q52-induced cerebellar dysfunction, microarray analysis and real-time RT-PCR assays were performed to identify altered cerebellar mRNA expressions of 10-11-month-old ataxin-7-Q52 transgenic mice. Ataxin-7-Q52 mice exhibited downregulated mRNA expressions of proteins involved in glutamatergic transmission, signal transduction, myelin formation, deubiquitination, axon transport, neuronal differentiation or glial functions and heat shock proteins. The involvement of transcriptional abnormality in initiating SCA7 pathological process was indicated by the finding that 6-month-old ataxin-7-Q52 transgenic mice, which did not display noticeable ataxic symptoms, exhibited dysregulated mRNA expressions. Our study suggests that polyglutamine-expanded ataxin-7-induced transcriptional dysregulation causes cerebellar dysfunction and ataxia.
authors.affiliation: Department of Anesthesiology, Chang Gung Memorial Hospital, Kwei-San, Tao-Yuan, Taiwan, ROC.
authors.forename: An-Hsun
authors.initials: AH
authors.lastname: Chou
authors.forename: Chia-Yang
authors.initials: CY
authors.lastname: Chen
authors.forename: Si-Ying
authors.initials: SY
authors.lastname: Chen
authors.forename: Wei-June
authors.initials: WJ
authors.lastname: Chen
authors.forename: Ying-Ling
authors.initials: YL
authors.lastname: Chen
authors.forename: Yi-Shin
authors.initials: YS
authors.lastname: Weng
authors.forename: Hung-Li
authors.initials: HL
authors.lastname: Wang
mesh_terms: D000818:Animals; D000067719:Ataxin-7; D001522:Behavior, Animal; D015153:Blotting, Western; D004195:Disease Models, Animal; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009419:Nerve Tissue Proteins / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000503:physiopathology; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; D009419:Nerve Tissue Proteins; D010455:Peptides; D012333:RNA, Messenger; C097188:polyglutamine