DAPK1-mediated parkin inactivation enhances neurotoxicity via MITOL-dependent degradation

Abstract

Parkinsons disease (PD) is characterized by progressive neurodegeneration and is marked by the formation of Lewy bodies, which are intracellular aggregates primarily composed of -synuclein. Mitochondrial dysfunction and impaired protein degradation pathways play critical roles in the progression of PD, contributing to the loss of dopaminergic neurons in the substantia nigra. Phosphorylation of -synuclein promotes its aggregation, underscoring its role in disease progression. Parkin, an E3 ubiquitin ligase, is considered to be a pleiotropic, neuroprotective protein that modulates the mitochondrial quality control as well as metabolic turnover and the accumulation of -synuclein. Death-associated protein kinase 1 (DAPK1), involved in controlling apoptosis and autophagy, has recently emerged as an important factor in neurodegeneration. While DAPK1 is implicated in Alzheimers disease through its role in tau aggregation and amyloid-{beta} production, we demonstrate that DAPK1 plays a role in PD by phosphorylating parkin at Ser136 and Ser198. This phosphorylation causes the mitochondrial transport of parkin, enhancing interaction with mitochondria-localized E3 ubiquitin ligase MITOL and consequently leading to the degradation of parkin. As parkin is critical for neuroprotection, its degradation exacerbates the toxic effect of 6-hydroxydopamine, further compromising neuronal survival. These results indicate that DAPK1 acts as a previously unrecognized modulator of parkin and a key contributor to PD pathogenesis, bridging pathways of mitochondrial dysfunction, -synuclein aggregation, and neuronal cell death.