alpha-Synuclein as a Membrane Binding Protein (Oral Communication)

FALOMIR LOCKHART LJ; SHVADCHAK VV; JOVIN TM

Munich

Workshop; Toxic Proteins Consortium Meeting; 2011

Max Planck Society - Toxic Proteins Consortium

Parkinson Disease (PD) is a progressive neurodegenerative condition present in more than 1% of the population above 60 years. PD is histologically defined by intracellular amyloid aggregates of proteins and lipids and most clinical symptoms arise after the selective loss of dopaminergic neurons of the substantia nigra. The protein alpha-Synuclein (aSyn) is the most abundant component in the amyloid aggregates and has been identified as a key player in the development of PD and other neuropathies. New data point towards early intermediates rather than amyloid fibrils as the “culprits”. Furthermore, oxidative stress is considered critical and lipid oxidation has been suggested to have also a central etiological role. Nevertheless, a comprehensive description of the relationship between amyloid aggregates and selective neuronal death is still missing. The aSyn is known to be able to adopt different conformations, and particularly in the presence of phospholipid bilayer, it shows rich -helix structure. Some of the clinical mutations described so far are believed to alter these properties affecting the distribution and/or function of the aSyn. Moreover, even though it has been suggested that it may participate in organization synaptic button, in the release of neurotransmitter and in intracellular vesicle traffic, the specific function/s of aSyn remain elusive. Here we present a systematic analysis of aSyn membrane interaction that allowed us to understand better how the protein responds to different lipidic stimuli, analyzing the relative affinity for different composition of membranes, the migration between different phospholipid interfaces and the effect of free fatty acids on the aggregation of aSyn. Our findings provide insight into the relationship between membrane physical properties and aSyn binding affinity and dynamics that presumably define protein localization in vivo and, thereby, the role of aSyn in the pathology of PD, as well as in its physiological repertoire.