Pathogenetic mechanisms of familial Parkinson’s disease: wt and A30P alpha-synucleins affect the structure of microfilaments and intermediate filaments. Pathways and effects on cytoskeletal dynamics

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by tremor, muscular rigidity and difficulty in initiating motor activity. It is observed in approximately 1% of the population over age 55. PD can be defined in biochemical terms as a dopamine-deficiency state resulting from degeneration of dopamine neurons. The strategy for treating PD has been to restore the dopamine deficit in the brain by pharmacological means or by neural grafting of dopamine-containing cells. The causes of neuronal cells death in PD are still poorly understood. Three different mutations were identified in the alpha-synuclein (Syn) gene in different families with early-onset PD. Moreover, Syn is present at very high levels in intracellular inclusions found in neurons of patients with PD. The pathogenesis of familial PD could be due to a loss of function of the mutated Syn protein, and a disturbance of Syn synthesis/turnover could play a role in conventional PD. This brings to the question of what is the physiological function of Syn. Syn is localized in the presynaptic terminals in neurons, in an ideal position to control neurotransmitter release. Suppression of the protein expression in mice or in cultured neuronal cells leads to alterations in the rate of neurotransmitter release, and the increase of the protein expression in cells induce a block in release. Here I propose to investigate the effect of Syn on two different cytoskeletal elements, the microfilaments and the intermediate filaments, which have a key role in the regulation of synaptic functions such as neurotransmitter release and neuronal regeneration. Once the physiological function of the protein will be established, I will test if the Syn mutants have lost or change their function. The understanding of the mechanism responsible of the neuronal cells dysfunction and subsequent degeneration will provide new clues to a more effective and long-lasting therapy for PD.