Neuropathology of α‐synuclein propagation and braak hypothesis

Abstract Parkinson's disease is a progressive neurodegenerative disorder with multiple factors contributing to increasing severity of pathology in specific brain regions. The Braak hypothesis of Lewy pathology progression in Parkinson's disease proposes a systematic spread of α‐synuclein that can be staged, with the later stages correlating with clinical aspects of the disease. The spread of pathology through the different stages suggests progression, a theory that has proven correct from evidence of pathology in healthy neurons grafted into the brains of patients with Parkinson's disease. Progression of pathology occurs on a number of levels, within a cell, between nearby cells, and then over longer distances throughout the brain, and evidence using prion proteins suggests two dissociable mechanisms—intracellular toxicity versus a nontoxic infectious mechanism for propagation. In Parkinson's disease, intracellular changes associated with mitochondria and lysosome dysfunction appear important for α‐synuclein propagation, with high stress conditions favoring mitochondrial cell death mechanisms. Functional neurons appear necessary for propagation. Unconventional exocytosis releases α‐synuclein under stress conditions, and endocytic uptake occurs in nearby cells. This cell‐to‐cell transmission of α‐synuclein has been recapitulated in both cell culture and animal models, but the timeframe of transmission is considerably shorter than that observed in transplanted neurons. The time course of Lewy pathology formation in patients is consistent with the long time course observed in grafted neurons, and the restricted neuronal loss in Parkinson's disease is potentially important for the propagation of α‐synuclein through relatively intact circuits. © 2015 International Parkinson and Movement Disorder Society