The aggregation of alpha-synuclein is stimulated by FK506 binding proteins as shown by fluorescence correlation spectroscopy

FASEB J. 2006 Mar;20(3):524-6. doi: 10.1096/fj.05-5126fje. Epub 2006 Jan 12.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Escherichia coli Proteins / isolation & purification
  • Escherichia coli Proteins / pharmacology*
  • Escherichia coli Proteins / physiology
  • Humans
  • Microscopy, Electron
  • Nephelometry and Turbidimetry
  • Peptidylprolyl Isomerase / isolation & purification
  • Peptidylprolyl Isomerase / pharmacology*
  • Peptidylprolyl Isomerase / physiology
  • Protein Folding
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / drug effects
  • Spectrometry, Fluorescence
  • Tacrolimus / pharmacology
  • Tacrolimus Binding Protein 1A / pharmacology*
  • Tacrolimus Binding Protein 1A / physiology
  • alpha-Synuclein / chemistry*
  • alpha-Synuclein / drug effects
  • alpha-Synuclein / genetics
  • alpha-Synuclein / ultrastructure

Substances

  • Escherichia coli Proteins
  • Recombinant Fusion Proteins
  • SlyD protein, E coli
  • alpha-Synuclein
  • Tacrolimus Binding Protein 1A
  • Peptidylprolyl Isomerase
  • Tacrolimus