Abstract:
:Mutations in Parkin, an E3 ligase, which participates in the ubiquitin-proteasome system (UPS), cause juvenile onset Parkinson's disease (PD). Some mutants aggregate upon over-expression, but the effects of such aggregation on the UPS and neuronal survival have not been characterized. We show in this study that transient over-expression of wild type (WT) Parkin or various mutants in human neuroblastoma cells leads to localized accumulation of green fluorescent protein (GFP(u)), an artificial proteasomal substrate, indicative of UPS dysfunction. Parkin mutants, but not WT, aggregated, and GFP(u) and ubiquitin accumulated within such aggregates. Apoptotic death occurred only with mutant Parkin over-expression, and correlated with aggregation, but not GFP(u) accumulation. Enzymatic proteasomal activity was slightly increased with WT Parkin and decreased with mutant Parkin over-expression. This decrease was, at least in part, due to caspase activation. We conclude that mutant forms of Parkin can exert toxic effects on neuronal cells, possibly through their propensity to aggregate. Both WT and mutant forms can induce localized UPS dysfunction, likely through different mechanisms. This raises a note of caution regarding forced over-expression of Parkin as a neuroprotective strategy in PD or other neurodegenerative conditions and suggests a possible toxic gain of function for certain mutant forms of Parkin.
journal_name
J Neurochemjournal_title
Journal of neurochemistryauthors
Kyratzi E,Pavlaki M,Kontostavlaki D,Rideout HJ,Stefanis Ldoi
10.1111/j.1471-4159.2007.04620.xsubject
Has Abstractpub_date
2007-08-01 00:00:00pages
1292-303issue
4eissn
0022-3042issn
1471-4159pii
JNC4620journal_volume
102pub_type
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journal_title:Journal of neurochemistry
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journal_title:Journal of neurochemistry
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