Pathogenesis of neurodegenerative disorders: The role of alpha-Synuclein in vesicular transport systems

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Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and the dementia with Lewy bodies (DLB) gain growing importance in the increasing aged population. Lewy bodies (LBs) are observed in these diseases. PD and DLB have been recently categorized as "synucleiopathies" since LBs are mainly composed of insoluble a-synuclein protein aggregates. Despite the genetic linkage of alpha-synuclein to rare familial PD, its function remains unknown. Recently, an association of a-synuclein with vesicular transport processes was suggested. a-Synuclein binds to lipid membranes and synthetic vesicles and associates with key proteins of the synaptic vesicle recycling machinery and the axonal vesicular transport system. The aims of the phase I of the Emmy NoetherProgramm are: (I) to characterize the interactions of alphasynuclein with vesicle associated proteins and lipids, (II) to functionally evaluate the role of a-synuclein in vesicular transport processes in vitro and; (III) to assess these findings of the aim I and II in vivo, both in transgenic mice and in brain samples of PD, DLB, or AD. These experiments will help to clarify the role of alpha-synuclein in neuronal vesicular transport and provide an ideal tool of identify future therapeutic stratgies that will be the focus of phase II of the Emmy Noether-Programm.