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Human Molecular Genetics Advance Access originally published online on July 27, 2005
Human Molecular Genetics 2005 14(17):2571-2586; doi:10.1093/hmg/ddi292
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin

Sathya R. Sriram1,2, Xiaojie Li1,2,3, Han Seok Ko1,3, Kenny K.K. Chung1,3, Esther Wong6, Kah Leong Lim6, Valina L. Dawson1,2,3,4,5 and Ted M. Dawson1,2,3,4,*

1Institute for Cell Engineering, 2Cellular and Molecular Medicine Graduate Program, 3Department of Neurology and 4Department of Neuroscience and 5Department of Physiology Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA and 6Neurodegeneration Laboratory, National Neurosciences Institute, Singapore

* To whom correspondence should be addressed at: Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 N Broadway Street, Suite 731, Baltimore, MD 21205, USA. Tel: +1 4106143359; Fax: +1 4106149568; Email: tdawson{at}jhmi.edu

Received May 12, 2005; Accepted July 19, 2005

Mutations in parkin are largely associated with autosomal recessive juvenile parkinsonism. The underlying mechanism of pathogenesis in parkin-associated Parkinson's disease (PD) is thought to be due to the loss of parkin's E3 ubiquitin ligase activity. A subset of missense and nonsense point mutations in parkin that span the entire gene and represent the numerous inheritance patterns that are associated with parkin-linked PD were investigated for their E3 ligase activity, localization and their ability to bind, ubiquitinate and effect the degradation of two substrates, synphilin-1 and aminoacyl-tRNA synthetase complex cofactor, p38. Parkin mutants vary in their intracellular localization, binding to substrates and enzymatic activity, yet they are ultimately deficient in their ability to degrade substrate. These results suggest that not all parkin mutations result in loss of parkin's E3 ligase activity, but they all appear to manifest as loss-of-function mutants due to defects in solubility, aggregation, enzymatic activity or targeting proteins to the proteasome for degradation.


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