Role of Oligomeric alpha-Synuclein in Mitochondrial Membrane Permeabilization and Neurodegeneration in Parkinson's Disease

摘要

A growing body of evidence suggests that aggregation of alpha- synuclein might be the fundamental cause of many neurodegenerative diseases. Several groups have developed cell culture models to study the cytotoxic effect of alpha-synuclein, and some of them indeed have observed enhanced cell death when alpha-synuclein, especially its mutant forms, was overexpressed. However, the link between alpha-synuclein aggregation and cell death has not been clearly addressed in these model systems, nor are the molecular mechanisms underlying the toxicity known. From the studies of the current project, we have demonstrated that the formation of prefibrillar oligomeric alpha-synuclein aggregates is tightly associated with Golgi fragmentation and cell death in both neuronal and non-neuronal cell models, suggesting the prefibrillar intermediates as being pathogenic species. On the other hand, fibrillar inclusion bodies seem to be a consequence of cellular effort to remove toxic protein aggregates and damaged organelles from cytoplasm. Finally, we show that alpha-synuclein aggregation causes the disruption of the microtubule network and the intracellular trafficking, leading to Golgi fragmentation and neuritic degeneration. These data identify microtubule dysfunction as being the link between alpha-synuclein aggregation and neurodegeneration.