Donovan Nguyen

Introduction. Parkinson’s disease (PD) is a progressive, neurodegenerative disease characterized by both motor and non-motor deficits due to dopaminergic neuron loss in the substantia nigra pars compacta^7,9. Current treatment is mainly management of symptoms through administration of exogenous dopamine¹. Mitochondrial dysfunction has been associated with neurodegeneration in Parkinson’s disease for over 30 years¹⁰. Recent discoveries suggests that mitochondrial damage results in inflammatory responses that cause PD symptoms¹. Mitophagy is a form of autophagy that disposes of damaged mitochondria and is regulated by ubiquitin ligase and ubiquitin kinase, Parkin and PINK1 respectively¹. Methods. 12-week-old wild-type (WT) and PINK1^-/- mice were exercised to exhaustion for three days to acutely stress mitochondria¹. Mitophagy response was measured by PINK1 phosphorylation of Parkin which activates it to induce mitophagy¹. Chronic mitochondrial stress was examined in Parkin^-/- mice with mutated mitochondrial DNA¹. IL-6, IFNβ1, TNFα, IL-1β, CCL2, IL-12, IL-13, IL-17, CXCL1, and CCL4 serum levels at age 20 and 40 weeks old were measured against wild type mice to determine mitophagic activity¹. Other sources were reviewed to understand how Parkin and PINK1 can be manipulated by potential regulators (1-4). Results. Wild type mice that were exhausted had a significant increase in Parkin activation compared to PINK1^-/- mice (p-value<0.001)¹. Parkin^-/- mice with mutated mitochondrial DNA displayed significantly lower serum levels of cytokines as well in addition to dopaminergic neuron loss and motor disorders¹. In other words, PINK1 and Parkin are necessary to reduce inflammation caused by elevated levels of dysfunctional mitochondria in PD¹. Furthermore, STING is regulator of type I Interferon responses to DNA found in cytoplasm¹. Removal of STING in mice with mutated mitochondrial DNA and defective Parkin reduced inflammation and neurodegeneration while restoring motor function¹. In another study, Nip3-like protein X (Nix) maintains mitophagy in an asymptomatic PD carrier that has interrupted PINK1/Parkin pathway². The pathway can also be disrupted by elevated nitric oxide (NO) levels that result in S-nitrosylation and deactivation of PINK1³. Deubiquitinating enzymes (DUBs) control the extent of mitophagy by reversing the activation of Parkin⁴. USP33 is a specific DUB for Parkin and removal of USP33 enhances mitophagy through accelerating Parkin translocation to mitochondria⁴. Conclusion. Damaged mitochondria result in inflammatory responses that lead to PD phenotype¹. The mitophagic process can be manipulated from several candidates that alter regulators Parkin and PINK1. Treatment options beyond alleviating symptoms are still needed and further research into how inflammation mechanistically causes PD symptoms should be considered.

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