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- Title
Inhibition of FK506 Binding Proteins Reduces α-Synuclein Aggregation and Parkinson's Disease-Like Pathology.
- Authors
Gerard, Melanie; Deleersnijder, Angélique; Daniëls, Veronique; Schreurs, Sarah; Munck, Sebastian; Reumers, Veerle; Pottel, Hans; Engelborghs, Yves; den Haute, Chris Van; Taymans, Jean-Marc; Debyser, Zeger; Baekelandt, Veerle
- Abstract
α-Synuclein (α-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 α-SYN in vitro. We now established a neuronal cell culture model for synucleinopathy based on oxidative stress-induced α-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 α-SYN aggregation and neuronal cell death in this synucleinopathy model dose dependently. Knockdown of FKBP12 or FKBP52 reduced the number of α-SYN aggregates and protected against cell death, whereas overexpression of FKBP12 or FKBP52 accelerated both aggregation of α-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 α -SYN in adult mouse brain significantly reduced α-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.
- Subjects
BRAIN diseases; APOPTOSIS; ISOMERASES; LIGANDS (Biochemistry)
- Publication
Journal of Neuroscience, 2010, Vol 30, Issue 7, p2454
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.5983-09.2010