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Human Molecular Genetics Advance Access published online on July 27, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi292
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received May 12, 2005
Revised July 19, 2005
Accepted July 19, 2005

Article

Familial-associated Mutations Differentially Disrupt the Solubility, Localization, Binding and Ubiquitination Properties of Parkin

Sathya R. Sriram 1, Xiaojie Li 2, Han Seok Ko 3, Kenny K.K. Chung 3, Esther Wong 4, Kah Leong Lim 4, Valina L. Dawson 5, and Ted M. Dawson 6*

1 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
4 Neurodegeneration Laboratory, National Neurosciences Institute, Singapore
5 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
6 Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 N Broadway Street, Suite 731, Baltimore, MD 21205, USA; Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

* To whom correspondence should be addressed.
Ted M. Dawson, E-mail: tdawson{at}jhmi.edu


  Abstract

Mutations in parkin are largely associated with autosomal recessive juvenile parkinsonism (AR-JP). 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 the 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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