%0 Journal Article
%T Differential regulation of wild-type and mutant alpha-synuclein binding to synaptic membranes by cytosolic factors
%A Sabine Wislet-Gendebien
%A Naomi P Visanji
%A Shawn N Whitehead
%A Diana Marsilio
%A Weimin Hou
%A Daniel Figeys
%A Paul E Fraser
%A Steffany AL Bennett
%A Anurag Tandon
%J BMC Neuroscience
%D 2008
%I BioMed Central
%R 10.1186/1471-2202-9-92
%X In the present study, we analysed the ability of cytosolic factors to regulate ¦Á-syn binding to synaptic membranes. We show that co-incubation with brain cytosol significantly increases the membrane binding of normal and PD-linked mutant ¦Á-syn. To characterize cytosolic factor(s) that modulate ¦Á-syn binding properties, we investigated the ability of proteins, lipids, ATP and calcium to modulate ¦Á-syn membrane interactions. We report that lipids and ATP are two of the principal cytosolic components that modulate Wt and A53T ¦Á-syn binding to the synaptic membrane. We further show that 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16:0 PAF) is one of the principal lipids found in complex with cytosolic proteins and is required to enhance ¦Á-syn interaction with synaptic membrane. In addition, the impaired membrane binding observed for A30P ¦Á-syn was significantly mitigated by the presence of protease-sensitive factors in brain cytosol.These findings suggest that endogenous brain cytosolic factors regulate Wt and mutant ¦Á-syn membrane binding, and could represent potential targets to influence ¦Á-syn solubility in brain.The synuclein family of intrinsically unfolded proteins is composed of three homologous and evolutionarily-conserved members with poorly defined physiological roles [1]. Of these, ¦Á-synuclein (¦Á-syn) has gained particular prominence due to its abundance in nerve terminals and its association with multiple neurodegenerative disorders including Parkinson disease (PD) [2]. ¦Á-Syn behaves as a peripherally associated membrane protein and can stably interact with synthetic phospholipid vesicles containing negatively charged head groups [3] via its amino-terminal domain, an amphipathic region comprising almost two-thirds of the protein and containing seven copies of an 11-residue repeat sequence [4]. Whereas the freely diffusible form of ¦Á-syn is natively unfolded, the N-terminal repeat region adopts an ¦Á-helical conformation upon binding to artificial ves
%U http://www.biomedcentral.com/1471-2202/9/92