The Nigral Coup in Parkinson's Disease by α-Synuclein and Its Associated Rebels

The risk of Parkinson's disease increases with age. However, the etiology of the illness remains obscure. It appears highly likely that the neurodegenerative processes involve an array of elements that influence each other. In addition, genetic, endogenous, or exogenous toxins need to be considered as viable partners to the cellular degeneration. There is compelling evidence that indicate the key involvement of modified alpha-synuclein (Lewy bodies) at the very core of the pathogenesis of the disease. The accumulation of misfolded alpha-synuclein may be a consequence of some genetic defect or/and a failure of the protein clearance system. Importantly, alpha-synuclein pathology appears to be a common denominator for many cellular deleterious events such as oxidative stress, mitochondrial dysfunction, dopamine synaptic dysregulation, iron dyshomeostasis, and neuroinflammation. These factors probably employ a common apoptotic/or autophagic route in the final stages to execute cell death. The misfolded alpha-synuclein inclusions skillfully trigger or navigate these processes and thus amplify the dopamine neuron fatalities. Although the process of neuroinflammation may represent a secondary event, nevertheless, it executes a fundamental role in neurodegeneration. Some viral infections produce parkinsonism and exhibit similar characteristic neuropathological changes such as a modest brain dopamine deficit and alpha-synuclein pathology. Thus, viral infections may heighten the risk of developing PD. Alternatively, alpha-synuclein pathology may induce a dysfunctional immune system. Thus, sporadic Parkinson's disease is caused by multifactorial trigger factors and metabolic disturbances, which need to be considered for the development of potential drugs in the disorder.

Automated summary

The risk of developing Parkinson's disease increases with age, and the etiology of the disease remains unclear. Pathological changes, such as misfolded alpha-synuclein, play a key role in the disease's pathogenesis. Various factors combine to contribute to the development of Parkinson's disease, suggesting the need for consideration of multifactorial triggers and metabolic disturbances in drug development.