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Dysfunction of α‐synuclein, a 14 kDa presynaptic neuronal protein, has been implicated in the pathogenesis of a number of neurodegenerative disorders known as “α‐synucleinopathies”, which include Parkinson’s disease, dementia with Lewy bodies, multiple‐system atrophy, and others. Aggregated protein inclusions mainly containing aberrant α‐synuclein are the pathological hallmarks of these disorders. In understanding how α‐synuclein dysfunction occurs, increasing focus is being placed on its post‐translational modifications due to proteostatic deficits and hyperphosphorylation, which are involved in its abnormal aggregation resulting in formation of typical inclusions. Soluble oligomeric, not fully fibrillar α‐synuclein, is thought to be neurotoxic, with its main targets being the synapse, axons and glia. The effects of aberrant α‐synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitrative injuries, cytoskeletal effects, neuroinflammation, and energy deficiency. However, how α‐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 α‐synuclein in the etiology of both familial and sporadic Parkinson’s disease, possibly through effects on autophagy and lysosomal function, but the majority of PD cases may result from complex interactions between environmental factors and genetic background. The neuropathologies of Parkinson’s disease, Lewy body dementia, and relevant animal models are briefly summarized. Emerging evidence, in addition to synergistic interactions of α‐synuclein with various pathogenic proteins, suggests that prion‐like induction and transmission of α‐synuclein could lead to the spreading of pathology and disease progression. Intervention in the early aggregation pathway, modulation of phosphorylation, aberrant cellular effects, or secretion of α‐synuclein might be targets for neuroprotection and disease‐modifying therapeutic options.

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