Parkin is recruited into aggresomes in a stress-specific manner: over-expression of parkin reduces aggresome formation but can be dissociated from parkin's effect on neuronal survival.
Parkinson's disease (PD) is characterized by loss of dopamine neurons in the substantia nigra and the presence of cytoplasmic inclusions known as Lewy bodies (LBs). Mutations in parkin cause autosomal recessive juvenile parkinsonism (AR-JP) that is distinct from sporadic PD by the general absence of LBs. Several studies have reported that parkin is present in LBs of sporadic PD but the role of parkin in LB formation is unclear. Aggresomes are perinuclear aggregates representing intracellular deposition of misfolded protein. LBs and aggresomes have been reported to share a common biogenesis. We have investigated the role of parkin in aggresome formation. In human SH-SY5Y neuroblastoma cells we observe that endogenous parkin is present in aggresomes induced by a variety of stresses including dopamine, proteosome inhibition and a pro-apoptopic stimulus. We show that vimentin is invariably collapsed around the aggresome but that the detection of ubiquitin is variable depending on the stress. We show that cells that stably over-express human wild-type parkin form fewer aggresomes upon stress compared to cells that express vector alone whereas over-expression of AR-JP causing mutants of parkin have no effect on stress-induced aggresome formation. Finally, we show that the prevention of aggresome formation by over-expression of wild-type parkin is not always associated with a beneficial effect on neuronal survival. Our findings suggest that parkin is important for aggresome formation in human neuronal cells and may lead to a better understanding of the biogenesis of LBs in sporadic PD.
Muqit
Miratul M K
MM
Medical Molecular Biology Unit, Institute of Child Health, University College London, London, UK.
Davidson
Sean M
SM
Payne Smith
Martin D
MD
MacCormac
Luci P
LP
Kahns
Soren
S
Jensen
Poul H
PH
Wood
Nicholas W
NW
Latchman
David S
DS
D015153:Blotting, Western; D002470:Cell Survival; D004298:Dopamine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D022101:Microtubule-Organizing Center / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014746:Vimentin / Q000378:metabolism
D007976:Leupeptins; D014404:Tubulin; D025801:Ubiquitin; D014746:Vimentin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D019311:Staurosporine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D004298:Dopamine