THERAPEUTIC INTERVENTIONS FOR MITOCHONDRIAL DYSFUNCTIONS CAUSED BY ALPHA-SYNUCLEIN AGGREGATION IN PARKINSON’S DISEASE

Parkinson's disease (PD) is a neurodegenerative disorder denoted by the progressive loss of dopaminergic neurons in the substantia nigra, a brain structure found within the midbrain atop the brainstem. Characterized by tremors and muscular rigidity, the central pathological hallmark of PD is the gradual buildup of Lewy bodies (amyloidogenic fibrils) from the aggregation of α-synuclein, a presynaptic neuronal protein ubiquitous within midbrain neurons. Research has demonstrated that this aggregation disrupts mitochondrial function and homeostasis, causing cytotoxicity and producing excessive reactive oxygen species (ROS), which all lead to neuronal death through mitochondrial stress. Mitochondria homeostasis is crucial to cell life due to its nature of energy production and cell regulation. Through oxidative phosphorylation, mitochondria produce their predominant energy source, adenosine triphosphate (ATP). Neurons then use ATP as a neuromodulator, satisfying the high energy demands of action potentials from dopaminergic neurons. Recent research has proposed irisin, a common myokine (a polypeptide released from myosin during muscle contractions), as a therapeutic intervention to support this homeostatic state. Irisin has been shown to promote mitochondria biogenesis, mitigating the aforementioned dyshomeostatic mechanisms and thus acting as a neuroprotective agent against α-synuclein aggregation and PD. Irisin was able to do this by regulating dynamin-related protein 1 (Drp1) expression within neuron mitochondria, allowing a Goldilocks zone of mitochondria fission and fusion. This perfect balance between over- and under-expression guides this paper through the current medical literature on treatments focused on Drp1 expression in the mitochondria. By discussing the microbiology of PD, illustrating a comprehensive understanding of irisin, and delving into other treatments that may propose similar outcomes, this document will holistically introduce the possible future of PD treatments.