The physiological role of α-synuclein and its relationship to Parkinson's Disease

Abstract

The protein α-synuclein has a central role in the pathogenesis of Parkinson's disease (PD). In this review, we discuss recent results concerning its primary function, which appears to be on cell membranes. The pre-synaptic location of synuclein has suggested a role in neurotransmitter release and it apparently associates with synaptic vesicles because of their high curvature. Indeed, synuclein over-expression inhibits synaptic vesicle exocytosis. However, loss of synuclein has not yet been shown to have a major effect on synaptic transmission. Consistent with work showing that synuclein can promote as well as sense membrane curvature, recent analysis of synuclein triple knockout mice now shows that synuclein accelerates dilation of the exocytic fusion pore. This form of regulation affects primarily the release of slowly discharged lumenal cargo such as neural peptides, but presumably also contributes to maintenance of the release site. This article is part of the Special Issue "Synuclein".

Keywords: Lewy pathology; Parkinson's disease; fusion pore; regulated exocytosis; synaptic vesicle; synuclein.

Figure. The Role of Synuclein in Exocytosis

Diagram illustrates the docking of a dense core vesicle, its fusion with the plasma membrane and subsequent dilation of the exocytic fusion pore, resulting in full collapse of the vesicle into the plasma membrane.Over-expression of synuclein (α− and β−) inhibits regulated exocytosis without affecting the number of docked vesicles, suggesting that it acts at the step of membrane fusion.However, loss of the endogenous synucleins produces only a small increase in membrane fusion, suggesting that this may not be its physiological role.In contrast, loss of synuclein delays the release of peptide cargo from dense core vesicles, and increases the likelihood that the fusion pore will close (reverse reaction).Thus, synuclein normally serves to promote dilation of the fusion pore.