Impairment of microtubule-dependent trafficking by overexpression of α-synuclein

Abnormal accumulation of alpha-synuclein (alpha-syn) has been linked to several neurological disorders, including Parkinson's disease (PD). However, the underlying mechanism by which alpha-syn accumulation affects neuronal function and survival remains unknown. Here, we provide data suggesting a possible effect of aggregated a-syn on the microtubule (MT) network. Consistent with the MT dysfunction, we also observed other degenerative changes, such as neuritic degeneration, trafficking defects, and Golgi fragmentation, which are common pathological features shared by many human neurodegenerative diseases. Neuritic degeneration and Golgi fragmentation were confirmed in primary cultures of dorsal root ganglia (DRG) neurons overexpressing alpha-syn. This effect of alpha-syn seems to have some selectivity to the MT system, as actin microfilaments and MT-independent trafficking remain unaffected. Within the degenerating neurites, we found numerous spherical co-aggregates of alpha-syn and tubulins, from which actin was excluded. These studies suggest that the MT system is a potential target of alpha-syn, and impairment of this system might have impacts on neuronal structure and function.