Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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Pathogenic mutations inactivate parkin by distinct mechanisms

J Neurochem 92(1): 114-22

Authors/Editors: Henn IH
Gostner JM
Lackner P
Winklhofer KF
Publication Date: 2005
Type of Publication: Journal Article
Loss of parkin function is the major cause of autosomal recessive Parkinson's disease (ARPD). A wide variety of parkin mutations have been identified in patients; however, the pathophysiological mechanisms leading to the inactivation of mutant parkin are poorly understood. In this study we characterized pathogenic C- and N-terminal parkin mutants and found distinct pathways of parkin inactivation. Deletion of the C terminus abrogated the association of parkin with cellular membranes and induced rapid misfolding and aggregation. Four N-terminal missense mutations, located within the ubiquitin-like domain (UBL), decrease the stability of parkin; as a consequence, these mutants are rapidly degraded by the proteasome. Furthermore, we present evidence that a smaller parkin species of 42 kDa, which is present in extracts prepared from human brain and cultured cells, originates from an internal start site and lacks the N-terminal UBL domain.

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