Interaction between Parkin and α-Synuclein in PARK2-Mediated Parkinson's Disease

Parkin and alpha-synuclein are two key proteins involved in the pathophysiology of Parkinson's disease (PD). Neurotoxic alterations of alpha-synuclein that lead to the formation of toxic oligomers and fibrils contribute to PD through synaptic dysfunction, mitochondrial impairment, defective endoplasmic reticulum and Golgi function, and nuclear dysfunction. In half of the cases, the recessively inherited early-onset PD is caused by loss of function mutations in the PARK2 gene that encodes the E3-ubiquitin ligase, parkin. Parkin is involved in the clearance of misfolded and aggregated proteins by the ubiquitin-proteasome system and regulates mitophagy and mitochondrial biogenesis. PARK2-related PD is generally thought not to be associated with Lewy body formation although it is a neuropathological hallmark of PD. In this review article, we provide an overview of post-mortem neuropathological examinations of PARK2 patients and present the current knowledge of a functional interaction between parkin and alpha-synuclein in the regulation of protein aggregates including Lewy bodies. Furthermore, we describe prevailing hypotheses about the formation of intracellular micro-aggregates (synuclein inclusions) that might be more likely than Lewy bodies to occur in PARK2-related PD. This information may inform future studies aiming to unveil primary signaling processes involved in PD and related neurodegenerative disorders.

Automated summary

This review article examines the role of Parkin and alpha-synuclein in the pathophysiology of Parkinson's disease, particularly focusing on the PARK2 gene mutations causing early-onset PD and the interaction between parkin and alpha-synuclein in protein aggregation regulation. The study provides insights into the potential formation of intracellular micro-aggregates in PARK2-related PD, suggesting new avenues for research into primary signaling processes involved in PD and related neurodegenerative disorders.