Neuropathology of alpha-synuclein in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive movement disability accompanied by non-motor symptoms. The neuropathology hallmark of PD is the loss of dopaminergic neurons predominantly in the substantia nigra pars compacta and the presence of intracellular inclusions termed Lewy bodies (LBs), which are mainly composed of alpha-synuclein (alpha Syn). Detailed staging based on the distribution and progression pattern of alpha Syn pathology in the postmortem brains of PD patients revealed correlation with the clinical phenotypes but not invariably. Cumulative evidence from cell and animal studies has implied that alpha Syn propagation contributes to the anatomical spread of alpha Syn pathology in the brain. Here, we recount the studies over the past two centuries on the anatomopathological foundations of PD documented. We also review studies on the structural analysis of alpha Syn and LBs, Braak staging of alpha Syn pathology, the cell-to-cell propagation of alpha Syn as well as alpha Syn fibril polymorphisms, which underlie the phenotypic differences in synucleinopathies.