title: Reduction of Purkinje cell pathology in SCA1 transgenic mice by p53 deletion.
abstract: The expansion of a polyglutamine tract in the ataxin-1 protein beyond a critical threshold causes spinocerebellar ataxia type 1 (SCA1). To investigate the mechanism of neuronal degeneration in SCA1, we analyzed the phenotype of an SCA1 transgenic mouse model in the absence of p53, an important regulator of cell death. p53 deficiency did not affect the early features of SCA1 mice such as impaired motor coordination and ataxin-1 nuclear inclusion formation but caused a notable reduction in later pathological features, including Purkinje cell heterotopia, dendritic thinning, and molecular layer shrinkage. To determine if this protective effect was mediated by an anti-apoptotic property of p53 deficiency, we looked for apoptosis in SCA1 mice but failed to detect any evidence of it even in the presence of p53. We propose that p53 acts after the initial pathogenic events in SCA1 to promote the progression of neuronal degeneration in SCA1 mice, but this activity may be unrelated to apoptosis.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Shahbazian
authors.forename: H T
authors.initials: HT
authors.lastname: Orr
authors.forename: H Y
authors.initials: HY
authors.lastname: Zoghbi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D000067696:Ataxin-1; D000067528:Ataxins; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D004856:Postural Balance / Q000502:physiology; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53