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Identification and Characterization of a Novel Endogenous Murine Parkin Mutation

Identification and Characterization of a Novel Endogenous Murine Parkin Mutation

Chenere P Ramsey, Benoit I Giasson

J Neurochem. 2010 Apr;113(2):402-17.

PMID: 20089136

Abstract:

Various mutations in the PARK2 gene which encodes the protein, parkin, are causal of a disease entity-termed autosomal recessive juvenile parkinsonism. Parkin can function as an E3 ubiquitin-protein ligase, mediating the ubiquitination of specific targeted proteins and resulting in proteasomal degradation. Parkin is thought to lead to parkinsonism as a consequence of a loss in its function. In this study, immunoblot analyses of brain extracts from Balb/c, C57BL/6, C3H, and 129S mouse strains demonstrated significant variations in immunoreactivity with anti-parkin monoclonal antibodies (PRK8, PRK28, and PRK109). This resulted partly from differences in the steady-state levels of parkin protein across mouse strains. There was also a complete loss of immunoreactivity for PRK8 and PRK28 antibodies in C3H mice due to was because of a homologous nucleotide mutation resulting in an E398Q amino acid substitution. In cultured cells, parkin harboring this mutation had a greater tendency to aggregate, exhibited reduced interaction with the E2 ubiquitin-conjugating enzymes, UbcH7 and UbcH8, and demonstrated loss-of-function in promoting the proteosomal degradation of a specific putative substrate, synphilin-1. In situ, C3H mice displayed age-dependent increased levels of brain cortical synphilin-1 compared with C57BL/6, suggesting that E398Q parkin in these mice is functionally impaired and that C3H mice may be a suitable model of parkin loss-of-function similar to patients with missense mutations.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4248182	Anti-Parkin antibody, Mouse monoclonal			Price

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