Inclusion Body Formation and Neurodegeneration Are Parkin Independent in a Mouse Model of α-Synucleinopathy
Autor: | Kristy Bruno, Ted M. Dawson, Ellen J. Hess, Shaida A. Andrabi, Valina L. Dawson, Rainer von Coelln, Joseph M. Savitt, Roya Saffary, Kah-Leong Lim, Bobby Thomas, Michael K. Lee, Wanda Stirling |
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Rok vydání: | 2006 |
Předmět: |
Male
Aging Parkinson's disease Cytoplasmic inclusion Ubiquitin-Protein Ligases animal diseases Mutant Mice Transgenic Parkin Mice Ubiquitin medicine Animals Tissue Distribution Mice Knockout Genetics biology General Neuroscience Neurodegeneration Brain Parkinson Disease Articles medicine.disease Phenotype nervous system diseases Ubiquitin ligase Cell biology Disease Models Animal nervous system Mutation alpha-Synuclein biology.protein Female Lewy Bodies |
Zdroj: | The Journal of Neuroscience. 26:3685-3696 |
ISSN: | 1529-2401 0270-6474 |
Popis: | Mutations in the genes coding for alpha-synuclein and parkin cause autosomal-dominant and autosomal-recessive forms of Parkinson's disease (PD), respectively. Alpha-synuclein is a major component of Lewy bodies, the proteinaceous cytoplasmic inclusions that are the pathological hallmark of idiopathic PD. Lewy bodies appear to be absent in cases of familial PD associated with mutated forms of parkin. Parkin is an ubiquitin E3 ligase, and it may be involved in the processing and/or degradation of alpha-synuclein, as well as in the formation of Lewy bodies. Here we report the behavioral, biochemical, and histochemical characterization of double-mutant mice overexpressing mutant human A53T alpha-synuclein on a parkin null background. We find that the absence of parkin does not have an impact on the onset and progression of the lethal phenotype induced by overexpression of human A53T alpha-synuclein. Furthermore, all major behavioral, biochemical, and morphological characteristics of A53T alpha-synuclein-overexpressing mice are not altered in parkin null alpha-synuclein-overexpressing double-mutant mice. Our results demonstrate that mutant alpha-synuclein induces neurodegeneration independent of parkin-mediated ubiquitin E3 ligase activity in nondopaminergic systems and suggest that PD caused by alpha-synuclein and parkin mutations may occur via independent mechanisms. |
Databáze: | OpenAIRE |
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