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Synphilin-1 degradation by the ubiquitin-proteasome pathway and effects on cell survival.

Authors
Lee, G; Junn, E; Tanaka, M; Kim, YM; Mouradian, MM
Citation
Journal of neurochemistry, 83(2):346-352, 2002
Journal Title
Journal of neurochemistry
ISSN
0022-30421471-4159
Abstract
Parkinson's disease is characterized by loss of nigral dopaminergic neurons and the presence of cytoplasmic inclusions known as Lewy bodies. alpha-Synuclein and its interacting partner synphilin-1 are among constituent proteins in these aggregates. The presence of ubiquitin and proteasome subunits in these inclusions supports a role for this protein degradation pathway in the processing of proteins involved in this disease. To begin elucidating the kinetics of synphilin-1 in cells, we studied its degradation pathway in HEK293 cells that had been engineered to stably express FLAG-tagged synphilin-1. Pulse-chase experiments revealed that this protein is relatively stable with a half-life of about 16 h. Treatment with proteasome inhibitors resulted in attenuation of degradation and the accumulation of high molecular weight ubiquitinated synphilin-1 in immunoprecipitation/immunoblot experiments. Additionally, proteasome inhibitors stimulated the formation of peri-nuclear inclusions which were immunoreactive for synphilin-1, ubiquitin and alpha-synuclein. Cell viability studies revealed increased susceptibility of synphilin-1 over-expressing cells to proteasomal dysfunction. These observations indicate that synphilin-1 is ubiquitinated and degraded by the proteasome. Accumulation of ubiquitinated synphilin-1 due to impaired clearance results in its aggregation as peri-nuclear inclusions and in poor cell survival.
MeSH terms
Acetylcysteine/*analogs & derivatives/pharmacologyAnimalsBlotting, WesternCarrier Proteins/genetics/*metabolismCell LineCell Survival/drug effects/physiologyCysteine Endopeptidases/*metabolismCysteine Proteinase Inhibitors/pharmacologyDimethyl Sulfoxide/pharmacologyHumansInclusion Bodies/metabolismKidney/chemistry/cytology/drug effects/metabolismLeupeptins/pharmacologyMacromolecular SubstancesMiceMultienzyme Complexes/antagonists & inhibitors/*metabolismNerve Tissue Proteins/genetics/*metabolismNeuroblastoma/metabolismPrecipitin TestsProteasome Endopeptidase ComplexProtein Processing, Post-Translational/drug effects/*physiologySynucleinsTransfectionUbiquitin/*metabolismalpha-Synuclein
PMID
12423244
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Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
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