Annual Meeting of the Society for Neuroscience edition:36 location:Atlanta, USA date:14-18 October 2006
Aggregation of alpha-synuclein plays a key role in Parkinson’s disease (PD). We have studied a-SYN aggregation in vitro using fluorescence correlation spectroscopy (FCS) and turbidity measurements. The aggregation process was clearly accelerated by addition of FK506 binding proteins (FKBPs). FKBPs are members of the immunophilins, enzymes that bind to immunosuppressant drugs and have a peptidyl-prolyl isomerase (PPIase) or rotamase activity. The accelerated aggregation of alpha-synuclein was observed both with E. coli SlyD FKBP and with human FKBP12 and was counteracted by FK506, a specific inhibitor of FKBP. The alpha-synuclein aggregates formed in the presence of FKBP12 showed fibrillar morphology. The rotamase activity of FKBP apparently accelerates the folding and subsequent aggregation of alpha-synuclein. Since FK506 and other non-immunosuppressive FKBP inhibitors are known to display neuroregenerative and neuroprotective properties in disease models, the observed inhibition of rotamase activity and alpha-synuclein aggregation, may explain their mode of action. Our results open perspectives for the treatment of PD with immunophilin ligands that inhibit a specific member of the FKBP family.