Stress-induced phospho-ubiquitin formation causes parkin degradation

Abstract

Mutations in the E3 ubiquitin ligase parkin are the most common known cause of autosomal recessive parkinsonism. Multiple types of stress decrease parkin protein levels, an effect that may be relevant to sporadic Parkinson's disease (PD), but the mechanism(s) involved in this loss remain largely unclear. We sought to elucidate these mechanisms using a PD-relevant stressor, L-DOPA, the precursor to dopamine, which forms reactive oxygen species (ROS) as well as toxic quinones via auto-oxidation. We find that L-DOPA causes parkin loss through both an oxidative stress-independent and an oxidative stress-dependent pathway. Characterization of the latter reveals that it requires both the kinase PINK1 and parkin's interaction with phosphorylated ubiquitin (phospho-Ub) and is mediated by proteasomal degradation.Surprisingly, mitochondrial parkin activity and autoubiquitination as well as mitophagy are not required for such loss. During stress induced by the oxidative stressor hydrogen peroxide or the metabolic uncoupler CCCP, parkin degradation also requires its association with phospho-Ub, indicating that this mechanism is broadly generalizable. As oxidative stress, metabolic dysfunction and phospho-Ub levels are all elevated in PD patients, we suggest that these changes may lead to the loss of parkin expression in PD.

The function of SUMOylation and its crucial roles in the development of neurological diseases

“…Parkin is a ubiquitin E3 ligase with a special role in the molecular mechanism of general neurodegeneration. 106 Mutations in the parkin gene have been implicated in autosomal recessive juvenile parkinsonism, an early onset and common familial form of PD. 107 RanBP2 localizes in the cytoplasmic filament of the nuclear pore complex and belongs to the SUMO E3 ligase family.…”

Mitochondrial quality control: from molecule to organelle

“…Recently, Kovalchuke and colleagues have demonstrated that other more physiological oxidative stressors like L-DOPA, lead to Parkin degradation. Although the exact mechanism of how Parkin is degraded following L-DOPA remains unclear, they show that PINK1 and phospho-Ub are involved in this pathway [175], demonstrating a similar mechanism to other mitochondrial stressors such as CCCP (mitochondrial uncoupler) [156]. This study suggests that oxidative stress or phospho-Ub may contribute to the loss of Parkin in PD.…”