To meet our goals, it is necessary to combine biochemical, biophysical, cellular analysis, molecular biology, genetic, in vivo, and behavioral strategies. Our efforts are focused on finding molecular targets that can be modified in a controlled manner in order to discover potential therapies that can diminish the progression of PD. The complexity of Parkinson's disease (PD) demands to be investigated at different levels in order to understand the nature of this catastrophic neurological motor impairment and propose valid therapies that can stop the neuronal degeneration. The results of our studies yield insights into the molecular basis for the neurotoxicity of A53E and shed light on a potential role for membrane-induced aSyn aggregation in PD pathogenesis in vivo, thus setting the stage for developing therapies to slow neurodegeneration in the brains of PD patients. To further address this hypothesis, we characterized a new familial PD mutant form of aSyn, A53E, in terms of its propensity to undergo membrane-induced aggregation and elicit neurotoxicity, based on the rationale that the introduction of a negatively charged residue at position 53 could potentially interfere with aSyn-membrane interactions. Data obtained by our group and others suggest that a disruption of interactions between aSyn and phospholipid membranes leads to a shift to an ‘exposed’ conformation that favors aggregation of the protein at membrane surfaces2.
However, mechanisms by which aSyn forms neurotoxic aggregates in PD are poorly understood. Neuropathological findings suggest that aggregated aSyn is involved in neuronal cell death.
Parkinson’s disease (PD) is characterized by the presence in post-mortem brains of Lewy bodies with aggregated forms of alpha-synuclein (aSyn), a presynaptic protein that exists as both cytosolic and membrane-bound forms.
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