Human Molecular Genetics Advance Access originally published online on September 30, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 22 2957-2965
DOI: 10.1093/hmg/ddg328
© 2003 Oxford University Press
RING finger 1 mutations in Parkin produce altered localization of the protein
1Laboratory of Neurogenetics, National Institute on Aging, 9000 Rockville Pike, Bethesda, MD 20892, USA, 2Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA and 3Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
Received July 11, 2003; Revised August 27, 2003; Accepted September 18, 2003
The Parkin gene (PRKN) encodes an E3 protein–ubiquitin ligase for which loss of function is associated with autosomal-recessive juvenile (<20 years) and early-onset Parkinsonism (<45 years). Although detailed pathological reports are scarce, brains from patients with homozygous exonic deletions demonstrate neuronal loss in the substantia nigra, albeit without the Lewy body pathology characteristic of idiopathic Parkinson's disease. However, there are rare descriptions of more florid pathology, including Lewy bodies and tau positive astrocytes in individuals with compound heterozygous mutations. In the present study we examined whether PRKN point mutations, leading to amino acid substitutions, may alter the cellular distribution of the protein produced. Wild-type Parkin was homogeneously distributed throughout the cytoplasm with a small amount of protein in the nucleus after transfection into human embryonic kidney cells. Mutant isoforms with A82E, G328E and C431F amino acid substitutions were also normally distributed. However, two mutant isoforms, R256C and R275W, within RING finger 1 of the Parkin protein (238–293 amino acids), produced an unusual distribution of the protein, with large cytoplasmic and nuclear inclusions. We have replicated this observation in primary cultured neurons and demonstrate, by the accumulation/co-localization of cytoskeletal protein vimentin, that the inclusion bodies are aggresomes, a cellular response to misfolded protein.
* To whom correspondence should be addressed. Tel: +1 9049530158; Fax: +1 9049537370; Email: farrer.matthew{at}mayo.edu
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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