Human Molecular Genetics Advance Access originally published online on November 25, 2003
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Human Molecular Genetics, 2004, Vol. 13, No. 1 117-135
DOI: 10.1093/hmg/ddh012
© 2004 Oxford University Press
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
1Medical Molecular Biology Unit, Institute of Child Health, University College London, London, UK, 2Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK, 3Neural Plasticity Unit, Institute of Child Health, University College London, London, UK, 4Department of Medical Biochemistry, Building 170, University of Aarhus, DK-8000 Aarhus-C, Denmark and 5Birkbeck, University of London, London, UK
Received September 24, 2003; Accepted November 6, 2003
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.
* To whom correspondence should be addressed at: Birkbeck, University of London, Malet Street, London WC1E 7HX, UK. Tel: +44 2076316274; Fax: +44 2076316259; Email: d.latchman{at}bbk.ac.uk
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