Sirtuins in Parkinson's disease: Molecular mechanisms and pathophysiological roles

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is associated with mitochondrial dysfunction, oxidative stress, neuroinflammation, and abnormal protein aggregation. The silent information regulator 2 (Sir2) family of proteins, known as sirtuins (SIRT1 - SIRT7), is nicotinamide adenine dinucleotide (NAD⁺)-dependent histone deacetylases that regulate important signal transduction pathways in both prokaryotes and eukaryotes. An increasing number of studies revealed that sirtuins play diverse roles in cellular homeostasis, such as metabolic regulation, oxidative stress response, apoptosis, organelle protection, and gene stability. Intriguingly, growing evidence suggests that sirtuins may serve as pivotal molecular mediators in PD, yet a comprehensive synthesis of their roles in this disorder is lacking. Although the precise pathogenesis of PD remains unmapped, identifying common molecular nodes could offer effective therapeutic strategies. In this review, we present the first systematic integration of current knowledge on the distinct contributions of individual sirtuins to PD pathophysiology offering promising molecular targets for the treatment of PD. Unlike previous studies focusing on isolated aspects of sirtuin biology, our work uniquely consolidates the multifaceted mechanisms by which sirtuins modulate PD, offering a holistic perspective on their therapeutic potential. We underscore the transformative potential of sirtuin modulation, positioning a promising and unexplored frontier in neurodegenerative disease therapy. This work aims to provide new insights into potential sirtuin-targeted therapy of PD.