Amyloidogenesis is the key pathological phenomenon commonly observed in various neurodegenerative disorders. alpha-Synuclein is the major constituent of Lewy bodies as a common pathological signature of Lewy body diseases (LBDs) including Parkinson's disease (PD), PD with dementia (PDD), and Dementia with Lewy bodies (DLB). As proteins unfold, they would result in producing either ordered or disordered aggregates unless they are folded back to the native state by molecular chaperones or removed via proteolytic degradation. alpha-Synuclein known as a natively unfolded protein has self-assembled into the ordered protein aggregates of amyloid fibrils which comprise the radiating filaments found in Lewy bodies. Amyloid fibrils are generated via either a template-dependent or template-independent mechanism. The prevalent nucleation-dependent fibrillation accelerates the assembly process in the presence of seeds such as prefibrillar species. As a template-independent process, we have recently proposed the double-concerted fibrillation mechanism in which the oligomeric species of alpha-synuclein act as a growing unit to form the mature fibrils. Despite insufficient understanding of the toxic causes of alpha-synuclein, the oligomeric species have been suggested to be responsible for the cellular degeneration by influencing membrane stability while leaving the amyloid fibrils as a detoxification end product. Alternatively, the transition process from the oligomers to the fibrils has been proposed to affect cell viability. It is, therefore, expected to develop prophylactic and therapeutic strategies toward the synucleinopathies by studying cellular function of alpha-synuclein, molecular mechanism of its assembly into the amyloid fibrils, and their effects on cellular biogenesis. By studying cellular function of alpha-synuclein, its molecular mechanism of assembly into amyloid fibrils and their effects on cellular biogenesis, progress of prophylactic and therapeutic strategies toward synucleinopathy can be seen.
alpha-Synuclein ; Amyloid ; Amyloidosis ; Cell Survival ; Dementia ; Lewy Bodies ; Membranes ; Molecular Chaperones ; Neurodegenerative Diseases ; Parkinson Disease ; Proteins ; Seeds ; Organelle Biogenesis