The role of α-synuclein in neurodegeneration - An update

Genetic, neuropathological and biochemical evidence implicates alpha-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant alpha-synuclein are widely accepted as morphological hallmarks of alpha-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. alpha-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and alpha-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in beta-pleated aggregation resulting in formation of typical inclusions. The physiological function of alpha-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar alpha-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant alpha-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in alpha-synucleinopathies. However, how alpha-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding alpha-synuclein in the etiology of Parkinson's disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of alpha-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of alpha-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of alpha-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of alpha-synuclein might be targets for neuroprotection and disease-modifying therapy.