Parkin‐mediated regulation of mitochondrial dynamics

Parkinson’s disease (PD) is a slowly progressive neurodegenerative disorder and is characterized clinically by motor dysfunction which typically manifests as bradykinesia, tremor, rigidity and postural/gait abnormalities (Lang and Lozano 1998a,b). The majority of cases of the disorder occurs sporadically and are of unknown cause. However, in approximately 10–15% of all cases of PD, there is good evidence for a gene-related etiology. Indeed, in recent years, several loci and mutations in various genes have been identified as the cause of rare familial forms of PD (Bras and Singleton 2009). Since 1997, an early-onset form of PD, referred to as autosomal recessive juvenile parkinsonism (AR-JP), has repeatedly been linked to chromosome 6q25.2–q27 (PARK 2) (Matsumine et al. 1997). This locus hosts a gene that encodes for a 465 amino acid/52 kDa protein called parkin (Kitada et al. 1998). Studies have shown that parkin is an E3 ubiquitin ligase (Shimura et al. 2000), a component of the ubiquitin-proteasome system, but it remains unclear as to how mutations in this gene alter protein degradation and other cellular activities, and thereby lead to the pathological changes that underlie AR-JP. In this issue of the journal, Glauser et al. (2011) provide important insights into the role of parkin in normal cellular function and how mutations in the protein may lead to neuronal death in PD. It was shown that parkin interacts with mitochondrial fusion factors (Mfn1 and 2), and polyubiquitinates Mfn1 which enhances its proteasomal degradation, in Human SH-SY5Y neuroblastoma cells in culture. However, PD-related mutations in parkin attenuate the ubiquitination of Mfn1. Based on these findings, Glauser et al. (2011) suggest that there is a close relationship between parkin and mitochondrial dynamics, and that mutations in the protein alter mitochondrial fission/fusion leading to neuronal death. The results in this build upon and extend current understanding of the role that parkin may play in cellular activity and degeneration. Parkin has been shown to ubiquitinate a variety of substrates (e.g. synphilin-1, CDCrel-1, and an O-glycosylated isoform of alpha-synuclein), but it remains unclear which, if any, of these substrates are key to its mechanism of action (Dawson and Dawson 2010). The demonstration in the present study that Mfn1 is ubiquitinated by parkin adds to this growing list of substrates, as well as providing a support for a link between parkin function and mitochondrial biology. An intriguing possibility is that wildtype parkin normally mediates the ubiquitination and degradation of mitofusins which blocks the fusion of damaged mitochondria, thereby facilitating their segregation and removal by the autophagic system (Gegg et al. 2010). Conversely, mutations in parkin, which is known to cause a loss of function of the protein, may impair its ability to regulate mitochondrial dynamic, thus leading to the accumulation of defective mitochondria and altered cell viability as suggested in the present study by Glauser and colleagues. While the findings by Glauser et al. (2011) provide important new insights into the biology of parkin, it is quite possible that other pathways contribute to the mechanism by which alterations lead to pathogenesis (Dawson and Dawson 2010). For example, mutations in parkin have been shown to impair its ability to mediate the ubiquitination and clearance of substrates which can accumulate, aggregate and induce proteolytic stress or other cytotoxic (Dawson and Dawson 2010). Indeed, Shin et al. (2011) recently identified a novel parkin interacting substrate (PARIS) whose levels are normally regulated by parkin-mediated ubiquitination and degradation. It was shown that loss of parkin activity causes the accumulation of PARIS, which represses transcriptional activities, and thereby induces dopamine cell loss in models of PD (Shin et al. 2011). Thus, the pathogenesis of AR-JP appears to be complex, involving interference with mitochondrial dynamics as well as other parkin-related pathways.