Title: Unraveling the role of peptidyl-prolyl isomerases in the aggregation of alpha-synuclein
Authors: Deleersnijder, Angélique
Gérard, Melanie
Debyser, Zeger
Baekelandt, Veerle #
Issue Date: Sep-2010
Publisher: John Wiley & Sons
Host Document: Movement Disorders vol:25 pages:S622-S622
Conference: World Parkinson Congress edition:2 location:Glasgow, UK date:28 September-1 October 2010
Article number: P03.01
Abstract: Background: FK506 Binding Proteins (FKBPs) belong to the immunophilins, enzymes with a peptidyl-prolyl isomerase (PPIase) activity that are inhibited by immunosuppressive drugs such as FK506. Their activity catalyzes the cis-to-trans conformational transition of proline during protein folding. In addition to FK506 Binding Proteins (FKBPs), the immunophilin family also includes cyclophilins and parvulins. We have previously shown that members of the FKBPs accelerate the aggregation of alpha-synuclein (a-SYN) in vitro (1). Furthermore, we demonstrated that FKBP12 and FKBP52 enhance the aggregation of a-SYN in a neuronal model for synucleinopathy (2). FK506, a specific inhibitor of this family of proteins, inhibited a-SYN aggregation and neuronal cell death in this cellular model and in a viral vector-based a-SYN mouse model (2).
Aim: In order to further validate FKBPs as a therapeutic target against a-synuclein neuropathology, we wondered whether specific FKBP(s) can accelerate a-SYN aggregation or whether this is a common property of the FKBP or even the PPIase family.
Results: Therefore, we decided to test some other physiologically relevant PPIases : FKBP38 and FKBP65, two FKBPs that are also enriched in the brain, Pin1, a member of the parvulin family, and cyclophilin A. We have studied the effect of these PPIases on a-SYN aggregation and apoptosis in vitro and in the cellular synucleinopathy model. We show that stable overexpression of several members of the FKBP family are able to enhance the aggregation of a-SYN and cell death in neuronal SHSY5Y cells, although FKBP12 remains the strongest stimulator.
Discussion: All data together move FKBP12 forward as the main PPIase influencing a-SYN aggregation and validate the protein as an interesting target for the development of specific inhibitors.
ISSN: 0885-3185
Publication status: published
KU Leuven publication type: IMa
Appears in Collections:Molecular Virology and Gene Therapy
Faculty of Medicine, Campus Kulak Kortrijk
Interdisciplinary Research Facility Life Sciences, Campus Kulak Kortrijk
Research Group for Neurobiology and Gene Therapy
# (joint) last author

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