A role for alpha-Synuclein in axon growth and its implications in corticostriatal glutamatergic plasticity in Parkinson's disease.

BACKGROUND: alpha-Synuclein (alpha-Syn) is a protein implicated in the pathogenesis of Parkinson's disease (PD). alpha-Syn has been shown to associate with membranes and bind acidic phospholipids. However, the physiological importance of these associations to the integrity of axons is not fully clear. METHODS: Biochemical, immunohistochemical and ultrastructural analyses in cultured neurons, transgenic mouse brains, PD and control human brains. RESULTS: We analyzed the ultrastructure of cross-sectioned axons localized to white matter tracts (WMTs), within the dorsal striatum of old and symptomatic alpha-Syn transgenic mouse brains. The analysis indicated a higher density of axons of thinner diameter. Our findings in cultured cortical neurons indicate a role for alpha-Syn in elongation of the main axon and its collaterals, resulting in enhanced axonal arborization. We show that alpha-Syn effect to enhance axonal outgrowth is mediated through its activity to regulate membrane levels of the acidic phosphatidylinositol 4,5-bisphosphate (PI4,5P2). Moreover, our findings link alpha-Syn- enhanced axonal growth with evidence for axonal injury. In relevance to disease mechanisms, we detect in human brains evidence for a higher degree of corticostriatal glutamatergic plasticity within WMTs at early stages of PD. However, at later PD stages, the respective WMTs in the caudate are degenerated with accumulation of Lewy pathology. CONCLUSIONS: Our results show that through regulating PI4,5P2 levels, alpha-Syn acts to elongate the main axon and collaterals, resulting in a higher density of axons in the striatal WMTs. Based on these results we suggest a role for alpha-Syn in compensating mechanisms, involving corticostriatal glutamatergic plasticity, taking place early in PD.