Common Mechanisms Underlying a-Synuclein-Induced Mitochondrial Dysfunction in Parkinson's Disease

Parkinson's disease (PD) is the most common neurological movement disorder characterized by the selective and irreversible loss of dopaminergic neurons in substantia nigra pars compacta resulting in dopamine deficiency in the striatum. While most cases are sporadic or environmental, about 10% of patients have a positive family history with a genetic cause. The misfolding and aggregation of a-synuclein (a-syn) as a casual factor in the pathogenesis of PD has been supported by a great deal of lit-erature. Extensive studies of mechanisms underpinning degeneration of the dopaminergic neurons induced by a-syn dysfunction suggest a complex process that involves multiple pathways, including mito-chondrial dysfunction and increased oxidative stress, impaired calcium homeostasis through membrane permeabilization, synaptic dysfunction, impairment of quality control systems, disruption of microtubule dynamics and axonal transport, endoplasmic reticulum/Golgi dysfunction, nucleus malfunction, and micro-glia activation leading to neuroinflammation. Among them mitochondrial dysfunction has been considered as the most primary target of a-syn-induced toxicity, leading to neuronal cell death in both sporadic and familial forms of PD. Despite reviewing many aspects of PD pathogenesis related to mitochondrial dys-function, a systemic study on how a-syn malfunction/aggregation damages mitochondrial functionality and leads to neurodegeneration is missing in the literature. In this review, we give a detailed molecular overview of the proposed mechanisms by which a-syn, directly or indirectly, contributes to mitochondrial dysfunction. This may provide valuable insights for development of new therapeutic approaches in relation to PD. Antioxidant-based therapy as a potential strategy to protect mitochondria against oxidative dam-age, its challenges, and recent developments in the field are discussed. & COPY; 2023 Elsevier Ltd. All rights reserved.

Automated summary

Parkinson's disease (PD) is a common neurological movement disorder characterized by the loss of dopaminergic neurons in the brain. A misfolded protein called a-synuclein (a-syn) has been identified as a key factor in the development of PD. This review discusses the mechanisms by which a-syn dysfunction leads to mitochondrial dysfunction, and the potential therapeutic approaches, such as antioxidant-based therapy, in PD treatment. The review emphasizes the importance of understanding the role of mitochondrial dysfunction in PD pathogenesis.