Mechanisms of Alpha-Synuclein Action on Neurotransmission: Cell-Autonomous and Non-Cell Autonomous Role

Mutations and duplication/triplication of the alpha-synuclein (alpha Syn)-coding gene have been found to cause familial Parkinson's disease (PD), while genetic polymorphisms in the region controlling the expression level and stability of alpha Syn have been identified as risk factors for idiopathic PD, pointing to the importance of wild-type (wt) alpha Syn dosage in the disease. Evidence that alpha Syn is present in the cerebrospinal fluid and interstitial brain tissue and that healthy neuronal grafts transplanted into PD patients often degenerate suggests that extracellularly-released alpha Syn plays a role in triggering the neurodegenerative process. alpha Syn's role in neurotransmission has been shown in various cell culture models in which the protein was upregulated or deleted and in knock out and transgenic animal, with different results on alpha Syn's effect on synaptic vesicle pool size and mobilization, alpha Syn being proposed as a negative or positive regulator of neurotransmitter release. In this review, we discuss the effect of alpha Syn on pre- and post-synaptic compartments in terms of synaptic vesicle trafficking, calcium entry and channel activity, and we focus on the process of exocytosis and internalization of alpha Syn and on the spreading of alpha Syn-driven effects due to the presence of the protein in the extracellular milieu.