Inhibition of FK506 binding proteins reduces alpha-synuclein aggregation and Parkinson's disease-like pathology.
alpha-Synuclein (alpha-SYN) is a key player in the pathogenesis of Parkinson's disease (PD). In pathological conditions, the protein is present in a fibrillar, aggregated form inside cytoplasmic inclusions called Lewy bodies. Members of the FK506 binding protein (FKBP) family are peptidyl-prolyl isomerases that were shown recently to accelerate the aggregation of alpha-SYN in vitro. We now established a neuronal cell culture model for synucleinopathy based on oxidative stress-induced alpha-SYN aggregation and apoptosis. Using high-content analysis, we examined the role of FKBPs in aggregation and apoptotic cell death. FK506, a specific inhibitor of this family of proteins, inhibited alpha-SYN aggregation and neuronal cell death in this synucleinopathy model dose dependently. Knockdown of FKBP12 or FKBP52 reduced the number of alpha-SYN aggregates and protected against cell death, whereas overexpression of FKBP12 or FKBP52 accelerated both aggregation of alpha-SYN and cell death. Thus, FK506 likely targets FKBP members in the cell culture model. Furthermore, oral administration of FK506 after viral vector-mediated overexpression of alpha-SYN in adult mouse brain significantly reduced alpha-SYN aggregate formation and neuronal cell death. Our data explain previously described neuroregenerative and neuroprotective effects of immunophilin ligands and validate FKBPs as a novel drug target for the causative treatment of PD.
Gerard
Melanie
M
Laboratories of Biochemistry, Interdisciplinary Research Centre, Katholieke Universiteit Leuven-Kortrijk, Flanders, Belgium.
Deleersnijder
Angélique
A
Daniëls
Veronique
V
Schreurs
Sarah
S
Munck
Sebastian
S
Reumers
Veerle
V
Pottel
Hans
H
Engelborghs
Yves
Y
Van den Haute
Chris
C
Taymans
Jean-Marc
JM
Debyser
Zeger
Z
Baekelandt
Veerle
V
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007211:Indoles; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000188:drug therapy / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D034741:RNA, Small Interfering / Q000494:pharmacology; D022061:Tacrolimus Binding Protein 1A / Q000172:deficiency; D022021:Tacrolimus Binding Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D007211:Indoles; D007381:Intermediate Filament Proteins; D034741:RNA, Small Interfering; D051844:alpha-Synuclein; C430456:desmuslin; C007293:DAPI; D008156:Luciferases; D022061:Tacrolimus Binding Protein 1A; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4