Alpha-synuclein: Pathology, mitochondrial dysfunction and neuroinflammation in Parkinson's disease

Parkinson's disease (PD) is a complex, chronic and progressive neurodegenerative disease. While the etiology of PD is likely multifactorial, the protein alpha-synuclein is a central component to the pathogenesis of the disease. However, the mechanism by which alpha-synuclein causes toxicity and contributes to neuronal death remains unclear. Mitochondrial dysfunction is also widely considered to play a major role in the underlying mechanisms contributing to neurodegeneration in PD. This review discusses evidence for the neuropathological role for alpha-synuclein in the dysfunction of dopamine neurons in PD. We also discuss insights into the structure, localization, and cellular roles for alpha-synuclein that may influence its aggregation properties, ultimately impacting its pathogenicity, role in lysosomal dysfunction and activation of the neuroimmune response. We further highlight recent evidence linking alpha-synuclein and mitochondrial dysfunction in neurodegeneration. Identifying the underlying mechanisms responsible for this bi-directional relationship between alpha-synuclein and mitochondrial dysfunction may provide new insights into the pathophysiology of PD. (c) 2017 mElsevier Inc. All rights reserved.