Parkin promotes cell survival via linear ubiquitination

Abstract

Mitochondrial dysfunction has been linked to the pathogenesis of Parkinson's disease (PD). PD‐associated mutants of Parkin show defects in mitophagy, suggesting that Parkin exerts its neuroprotective role by removal of damaged mitochondria. Muller‐Rischart et al (2013) now uncover an autophagy‐independent pathway involving Parkin‐mediated activation of the LUBAC ubiquitin ligase to prevent mitochondrial impairment and thereby to promote survival. PD represents the most common movement disorder and is caused by dopaminergic neurodegeneration. As the majority of cases arise sporadically, the identification of monogenetic variants marked the beginning of a new era in PD research. Loss‐of‐function mutations mapped to the Parkin ubiquitin ligase and PINK1 kinase loci were shown to cause autosomal recessive juvenile parkinsonism (Kitada et al , 1998). The generation of PINK1 and Parkin deletion mutants in Drosophila illustrated their requirement for the maintenance of mitochondrial integrity (Clark et al , 2006) and supported the notion that mitochondrial dysfunction is a major etiological factor in PD. These reports also demonstrated the genetic epistasis of PINK1 and Parkin, placing them in a common or converging pathway. Further studies revealed their involvement in the autophagic removal of damaged mitochondria (Narendra et al , 2008). PINK1 is selectively retained and stabilized at the outer membrane of depolarized mitochondria and serves as a signal for Parkin recruitment and activation. Subsequent ubiquitination of mitochondrial proteins by Parkin drives affected mitochondria into autophagosomes (Geisler et al , 2010). In addition, mounting evidence …