Title: Inhibition of FK506 binding proteins reduces alpha-synuclein aggregation and Parkinson's disease-like pathology
Authors: Gérard, Melanie
Deleersnijder, Angélique
Daniëls, Veronique
Schreurs, Sarah
Munck, Sebastian
Reumers, Veerle
Pottel, Hans
Engelborghs, Yves
Van Den Haute, Chris
Taymans, Jean-Marc
Debyser, Zeger
Baekelandt, Veerle # ×
Issue Date: Feb-2010
Publisher: Soc neuroscience
Series Title: Journal of neuroscience vol:30 issue:7 pages:2454-2463
Abstract: 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.
ISSN: 0270-6474
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Faculty of Medicine, Campus Kulak Kortrijk
Department of Human Genetics - miscellaneous
Research Group for Neurobiology and Gene Therapy
Biochemistry, Molecular and Structural Biology Section
Interdisciplinary Research Facility Life Sciences, Campus Kulak Kortrijk
Molecular Virology and Gene Therapy
× corresponding author
# (joint) last author

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