The role of the endolysosomal pathway in a-synuclein pathogenesis in Parkinson's disease

Parkinson's disease (PD) is a chronic neurodegenerative disease that is characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain (SNpc). Extensive studies into genetic and cellular models of PD implicate protein trafficking as a prominent contributor to the death of these dopaminergic neurons. Considerable evidence also suggests the involvement of a-synuclein as a central component of the characteristic cell death in PD and it is a major structural constituent of proteinaceous inclusion bodies (Lewy bodies; LB). a-synuclein research has been a vital part of PD research in recent years, with newly discovered evidence suggesting that a-synuclein can propagate through the brain via prion-like mechanisms. Healthy cells can internalize toxic a-synuclein species and seed endogenous a-synuclein to form large, pathogenic aggregates and form LBs. A better understanding of how a-synuclein can propagate, enter and be cleared from the cell is vital for therapeutic strategies.