The M458L missense mutation disrupts the catalytic properties of Parkin

Abstract

Parkin encodes an E3 ubiquitin ligase, and mutations affecting its catalytic potential are implicated in autosomal recessive Parkinson's disease (PD). The M458L mutation of parkin and its enzymatic effects require characterization. Therefore, we examined the enzymatic activity of Parkin with M458L mutation. We show that the M458L mutant retains its autoubiquitination potential in vitro but not in cells. Fas-associated factor 1 and p38 (substrates of Parkin) are able to bind to the M458L mutant in cells; however, these Parkin substrates are not ubiquitinated and degraded in M458L mutant-transfected cells. Moreover, M458L mutant fails to protect the mitochondria against hydrogen peroxide leading to cell death. Considering the role of mitochondrial dysfunction in PD pathogenesis, our results imply a causative role for the M458L mutation in neurodegeneration.

Parkin truncating variants result in a loss-of-function phenotype

“…Parkin can promote its self-ubiquitination and this activity has been used to measure the enzymatic function of parkin 13,14,21,24 . Therefore, we have investigated whether the N52Mfs*29 and L358Rfs*77 variants impair parkin self-ubiquitination activity in cells.…”