Origins and effects of extracellular alpha-synuclein: implications in Parkinson's disease.
Misfolding and abnormal aggregation of the neuronal protein alpha-synuclein has been implicated in the pathogenesis of Parkinson's disease and related neurological disorders, such as dementia with Lewy bodies. alpha-synuclein is a conventional cytosolic protein and is thought to exert its pathogenic function exclusively in the neuronal cytoplasm in a cell-autonomous manner. However, the current model is being challenged by a series of new observations that demonstrate the presence of alpha-synuclein and its aggregated forms in the extracellular fluid both in vivo and in vitro. Extracellular alpha-synuclein appears to be delivered by unconventional exocytosis of intravesicular alpha-synuclein, although the exact mechanism has not been characterized. Compared to the cytosolic alpha-synuclein, intravesicular alpha-synuclein is prone to aggregation and the potential source of extracellular aggregates. A number of tissue culture studies suggest that exposure to extracellular alpha-synuclein aggregates induces microglial activation, release of pro-inflammatory cytokines from astrocytes, and neurotoxicity. Thus, exocytosis of alpha-synuclein may be an important mechanism for amplifying and spreading degenerative changes from a small group of cells to its surrounding tissues, and it potentially provides therapeutic targets for halting the progression of the disease.
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D004660:Encephalitis / Q000378:metabolism / Q000503:physiopathology; D005089:Exocytosis / Q000502:physiology; D045604:Extracellular Fluid / Q000378:metabolism*; D005911:Gliosis / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D017628:Microglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism* / Q000503:physiopathology; D051844:alpha-Synuclein / Q000378:metabolism*
D051844:alpha-Synuclein