title: Comparative analysis of different peptidyl-prolyl isomerases reveals FK506-binding protein 12 as the most potent enhancer of alpha-synuclein aggregation.
abstract: FK506-binding proteins (FKBPs) are members of the immunophilins, enzymes that assist protein folding with their peptidyl-prolyl isomerase (PPIase) activity. Some non-immunosuppressive inhibitors of these enzymes have neuroregenerative and neuroprotective properties with an unknown mechanism of action. We have previously shown that FKBPs accelerate the aggregation of α-synuclein (α-SYN) in vitro and in a neuronal cell culture model for synucleinopathy. In this study we investigated whether acceleration of α-SYN aggregation is specific for the FKBP or even the PPIase family. Therefore, we studied the effect of several physiologically relevant PPIases, namely FKBP12, FKBP38, FKBP52, FKBP65, Pin1, and cyclophilin A, on α-SYN aggregation in vitro and in neuronal cell culture. Among all PPIases tested in vitro, FKBP12 accelerated α-SYN aggregation the most. Furthermore, only FKBP12 accelerated α-SYN fibril formation at subnanomolar concentrations, pointing toward an enzymatic effect. Although stable overexpression of various FKBPs enhanced the aggregation of α-SYN and cell death in cell culture, they were less potent than FKBP12. When FKBP38, FKBP52, and FKBP65 were overexpressed in a stable FKBP12 knockdown cell line, they could not fully restore the number of α-SYN inclusion-positive cells. Both in vitro and cell culture data provide strong evidence that FKBP12 is the most important PPIase modulating α-SYN aggregation and validate the protein as an interesting drug target for Parkinson disease.
authors.affiliation: Laboratory of Biochemistry, K. U. Leuven-Kortrijk, Etienne Sabbelaan 53, B-8500 Kortrijk, Flanders, Belgium.
authors.forename: Angélique
authors.initials: A
authors.lastname: Deleersnijder
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Van Rompuy
authors.forename: Linda
authors.initials: L
authors.lastname: Desender
authors.forename: Hans
authors.initials: H
authors.lastname: Pottel
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Veerle
authors.initials: V
authors.lastname: Baekelandt
authors.forename: Melanie
authors.initials: M
authors.lastname: Gerard
mesh_terms: D016923:Cell Death; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D055785:Gene Knockdown Techniques; D006801:Humans; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D022061:Tacrolimus Binding Protein 1A / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D022061:Tacrolimus Binding Protein 1A; D019696:Peptidylprolyl Isomerase