Genetics of α-Synuclein: The Prime Pathological Player of Parkinson's Disease

Parkinson's disease is a complex neurodegenerative disorder that results from the interplay of genetic, environmental, and age-associated factors. The characteristic pathological feature of the disease is the presence of aggregated forms of the intrinsically disordered protein α-synuclein. Protein aggregates eventually form Lewy bodies, which are associated with the death of dopaminergic neurons. Elevated expression, mutations in the coding sequence, increased misfolding, and decreased degradation contribute to the aggregation of α-synuclein, associated with the disease. Mutations in the SNCA gene, which encodes α-synuclein, are predominantly associated with the familial form of the disease. The majority of the identified mutations are located in the N-terminal region of the protein and are associated with either early- or late-onset of the disease. Studies using model organisms, cell lines, and animal models identified several cellular effects associated with mutated forms of the protein. In addition, the clinical phenotypes of the disease in patients with different mutations vary in intensity. Interestingly, although each mutation is associated with the disease, the resulting α-synuclein aggregation rate and effect on cellular pathways are variable. In this review, we aim to summarize these interesting alterations in the protein and the associated pathophysiology of the disease following a single amino acid change.