Pathogenic mutations inactivate parkin by distinct mechanisms.
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.
Henn
Iris H
IH
Department of Cellular Biochemistry, Max Planck Institute for Biochemistry, Martinsried, Germany.
Gostner
Johanna M
JM
Lackner
Peter
P
Tatzelt
Jörg
J
Winklhofer
Konstanze F
KF
D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D020868:Gene Silencing; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000235:genetics; D017384:Sequence Deletion; D024363:Transcription Initiation Site; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
D010446:Peptide Fragments; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex