Mechanisms Associated with PINK1 Variants in Parkinson's Disease.

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Parkinson's disease (PD) is a widespread and progressively debilitating neurodegenerative disorder with a growing global prevalence. While most cases are sporadic, loss-of-function variants in the PINK1 gene are a primary cause of autosomal recessive early-onset PD. This review critically explores the molecular mechanisms linking PINK1 dysfunction to PD, with a specific focus on the kinase's role in phosphorylating Ubiquitin and Parkin at the conserved Serine 65 (Ser65) residue. We discuss how this phosphorylation event acts as a molecular switch to recruit the novel autophagy receptors Optineurin (OPTN) and NDP52, thereby initiating mitophagy-a process often disrupted by pathogenic variants. Furthermore, we examine the emerging role of PINK1 in suppressing neuroinflammation via the STING pathway and evaluate the translational potential of targeting these molecular checkpoints for therapeutic intervention. These insights lay the groundwork for developing precision medicine strategies to address the urgent need for effective PD treatments.

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