The aggregation of alpha-synuclein is stimulated by FK506 binding proteins as shown by fluorescence correlation spectroscopy.
Aggregation of alpha-synuclein (alpha-SYN) plays a key role in Parkinson's disease (PD). We have used fluorescence correlation spectroscopy (FCS) to study alpha-SYN aggregation in vitro and discovered that this process is clearly accelerated by addition of FK506 binding proteins (FKBPs). This effect was observed both with E. coli SlyD FKBP and with human FKBP12 and was counteracted by FK506, a specific inhibitor of FKBP. The alpha-SYN aggregates formed in the presence of FKBP12 showed fibrillar morphology. The rotamase activity of FKBP apparently accelerates the folding and subsequent aggregation of alpha-SYN. 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-SYN 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.
Gerard
Melanie
M
Laboratory of Biomolecular Dynamics, K.U. Leuven, Leuven, Belgium.
Debyser
Zeger
Z
Desender
Linda
L
Kahle
Philipp J
PJ
Baert
Johan
J
Baekelandt
Veerle
V
Engelborghs
Yves
Y
D029968:Escherichia coli Proteins / Q000302:isolation & purification / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D008854:Microscopy, Electron; D009391:Nephelometry and Turbidimetry; D019696:Peptidylprolyl Isomerase / Q000302:isolation & purification / Q000494:pharmacology* / Q000502:physiology; D017510:Protein Folding; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000187:drug effects; D013050:Spectrometry, Fluorescence; D016559:Tacrolimus / Q000494:pharmacology; D022061:Tacrolimus Binding Protein 1A / Q000494:pharmacology* / Q000502:physiology; D051844:alpha-Synuclein / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics / Q000648:ultrastructure
D029968:Escherichia coli Proteins; D011993:Recombinant Fusion Proteins; C085606:SlyD protein, E coli; D051844:alpha-Synuclein; D022061:Tacrolimus Binding Protein 1A; D019696:Peptidylprolyl Isomerase; D016559:Tacrolimus