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The Journal of Biological Chemistry
Year: 2008 | Volume: 283 | Issue: 11 | Page No.: 6979 - 6987
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α-Synuclein Aggregates Interfere with Parkin Solubility and Distribution
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Kohichi Kawahara,
Makoto Hashimoto,
Pazit Bar-On,
Gilbert J. Ho,
Leslie Crews,
Hideya Mizuno,
Edward Rockenstein,
Syed Z. Imam
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Eliezer Masliah
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Abstract: Parkinson disease (PD) belongs to a heterogeneous group of neurodegenerative disorders with movement alterations, cognitive impairment, and α-synuclein accumulation in cortical and subcortical regions. Jointly, these disorders are denominated Lewy body disease. Mutations in the parkin gene are the most common cause of familial parkinsonism, and a growing number of studies have shown that stress factors associated with sporadic PD promote parkin accumulation in the insoluble fraction. α-Synuclein and parkin accumulation and mutations in these genes have been associated with familial PD. To investigate whether α-synuclein accumulation might be involved in the pathogenesis of these disorders by interfering with parkin solubility, synuclein-transfected neuronal cells were transduced with lentiviral vectors expressing parkin. Challenging neurons with proteasome inhibitors or amyloid-β resulted in accumulation of insoluble parkin and, to a lesser extent, α-tubulin. Similarly to neurons in the brains of patients with Lewy body disease, in co-transduced cells α-synuclein and parkin colocalized and co-immunoprecipitated. These effects resulted in decreased parkin and α-tubulin ubiquitination, accumulation of insoluble parkin, and cytoskeletal alterations with reduced neurite outgrowth. Taken together, accumulation of α-synuclein might contribute to the pathogenesis of PD and other Lewy body diseases by promoting alterations in parkin and tubulin solubility, which in turn might compromise neural function by damaging the neuronal cytoskeleton. These studies provide a new perspective on the potential nature of pathogenic α-synuclein and parkin interactions in Parkinson disease.
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