Outlook of PINK1/Parkin signaling in molecular etiology of Parkinson’s disease, with insights into <i>Pink1</i> knockout models
Zhangting Wang, See-Wing Chan, Hui Zhao, Kai-Kei Miu, Wai‐Yee Chan
Abstract
Parkinson’s disease (PD) relates to defective mitochondrial quality control in the dopaminergic motor network. Genetic studies have revealed that <i>PINK1</i> and <i>Parkin</i> mutations are indicative of a heightened propensity to PD onset, pinpointing mitophagy and inflammation as the culprit pathways involved in neuronal loss in the substantia nigra (SNpc). In a reciprocal manner, <i>LRRK2</i> functions in the regulation of basal flux and inflammatory responses responsible for PINK1/Parkin-dependent mitophagy activation. Pharmacological intervention in these disease-modifying pathways may facilitate the development of novel PD therapeutics, despite the current lack of an established drug evaluation model. As such, we reviewed the feasibility of employing the versatile global <i>Pink1</i> knockout (KO) rat model as a self-sufficient, spontaneous PD model for investigating both disease etiology and drug pharmacology. These rats retain clinical features encompassing basal mitophagic flux changes with PD progression. We demonstrate the versatility of this PD rat model based on the incorporation of additional experimental insults to recapitulate the proinflammatory responses observed in PD patients.