Toward a normal function for the synuclein proteins

Abstract

α‐Synuclein has received much attention in recent years because of its association with neurodegenerative disease. Mutations in the α‐synuclein gene are linked to some rare cases of early onset Parkinson's disease, and the α‐synuclein protein itself is abundant in intracellular inclusions typical of sporadic and familial Parkinson's disease, dementia with Lewy bodies, Down's syndrome, and multiple system atrophy. Our lab has focused on the biophysical attributes of α‐synuclein as a means to elucidate its normal cellular function. α‐Synuclein and its relatives, β‐ and γ‐synuclein, are abundant proteins of the nervous system, and their primary sequences are extremely well conserved, suggesting that specific molecular interactions may constrain their evolution. One candidate interaction is that which occurs between synucleins and phospholipid membranes. Each of the proteins possesses an apolipoprotein‐like N‐terminal domain of ∼ 100 amino acid which adopts a random coil conformation in solution, but folds into an amphipathic α‐helix upon association with phospholipid bilayers. We find that a similar conformational change can be driven by fatty acid micelles, and that association with α‐synuclein protects the fatty acids against oxidative damage. Drawing on these observations and on the published literature, this presentation will attempt to formulate a general hypothesis for synuclein function which accounts for the observed similarities between the synucleins and the exchangeable apolipoproteins.