Journal Article

RING finger 1 mutations in Parkin produce altered localization of the protein

Mark R. Cookson, Paul J. Lockhart, Chris McLendon, Casey O'Farrell, Michael Schlossmacher and Matthew J. Farrer

in Human Molecular Genetics

Volume 12, issue 22, pages 2957-2965
Published in print November 2003 | ISSN: 0964-6906
Published online November 2003 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddg328
RING finger 1 mutations in Parkin produce altered localization of the protein

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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.

Journal Article.  5151 words.  Illustrated.

Subjects: Genetics and Genomics

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