Objective/Rationale:
FK506 Binding Proteins (FKBPs) are enzymes that play a role in protein folding. FKBPs are highly expressed in human brain and are thought to be involved in neurodegenerative disorders, including Parkinson's disease (PD). FKBP inhibitors such as FK506 were shown to be protective in different models of brain injury and neurodegeneration, but the precise mechanism is not well understood. We have found that FK506 inhibits the aggregation of alpha-synuclein, which may help to explain its neuroprotective effects.
Project Description:
FKBPs belong to a family of about 15 related proteins. In this project, we aim to identify which member(s) of the FKBP family specifically affects alpha-synuclein neuropathology and toxicity. To do this, we will inhibit specific members of the FKBPs in a cellular model, and in a second phase in a pre-clinical model using viral vector technology. We will examine if one or more FKBP members can inhibit the aggregation of α-synuclein in these models, and whether this also ameliorates cell survival.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If we can confirm that inhibition of FKBPs can decrease α-synuclein aggregation and neuronal cell death, this offers a new avenue for a causal treatment for PD, which can hopefully stop or even reverse the disease process. Moreover, if we can identify which specific FKBP member is the major player, this should allow us to develop new drugs that specifically inhibit this FKBP.
Anticipated Outcome:
From this project we hope to learn if one or more FKBPs influence α-synuclein aggregation and neurotoxicity in a pre-clinical model for PD. We should also find out whether inhibition of these FKBPs in the brain can stop the disease process. Furthermore, if we can identify which FKBP has the strongest effect on α-synuclein aggregation and neurotoxicity, this will guide future drug discovery projects targeting this FKBP.
Final Outcome
We have compared the effect of several physiologically relevant peptidylprolyl isomerases (PPIases) on alpha-synuclein (a-SYN) aggregation in vitro. Among all PPIases tested, we could demonstrate that FKBP12 accelerated a-SYN aggregation the most (Deleersnijder A, et al. J Biol Chem. 2011). Next, we have tested the effect of these PPIases on a-SYN aggregation in cell culture. Therefore, we have co-expressed a-SYN and the different PPIases in human neuronal cell lines. Only members of the FKBP family enhanced the aggregation of a-SYN and cell death in a cellular high content assay, but FKBP12 turned out to be the most potent modulator. To further investigate the role of FKBP12 on a-SYN neuropathology in vivo, we have developed adeno-associated viral (AAV) vectors to inhibit FKBP12 in rodent brain. We could show that FKBP12 knockdown slows down the aggregation of a-SYN in a transgenic mouse model. These data support further research into FKBP12 as a novel therapeutic target for Parkinson’s Disease.
Publications
Deleersnijder A., Gérard M., Debyser Z. and Baekelandt V. The remarkable conformational plasticity of alpha-synuclein : blessing or curse? Trends in Molecular Medicine, invited review submitted.
Van der Perren A, Toelen J, Van Rompuy A S, Casteels C, Sarre S, Gerard M, Maris M, Casadei N, Nuber S, Himmelreich U, Osorio Garcia M G, Reumers V, De Loor H, Kuypers D R J, Bormans G, Van Laere K, Gijsbers R, Van den Haute C, Debyser Z, Baekelandt V. FK506 prevents neuroinflammation and dopaminergic neurodegeneration in an α-synuclein-based rat model for Parkinson’s disease. Submitted
Deleersnijder A., Desender L., Munck S., Pottel H., Buée L., Debyser Z., Baekelandt V. and Gerard M. (2011) Comparative analysis of different peptidyl-prolylisomerases reveals FK506-binding protein 12 as the most potent enhancer of α-synuclein aggregation. J. Biol. Chem., 286:26687-26701
Gerard M., Deleersnijder A., Demeulemeester J., Debyser Z. and Baekelandt V. (2011) Unraveling the role of peptidyl-prolyl isomerases in neurodegeneration. Molecular Neurobiology, 44:13-27
Oral Presentations
Van der Perren A1, Macchi F1, Toelen J2, Van Rompuy AS1, Casteels C3, Sarre S4, Gerard M5, Maris M2, Casadei N6, Nuber S6, Himmelreich U7, Osorio Garcia MI7, Reumers V1, de Loor H8, Kuypers DRJ8, Bormans G9, Van Laere K3, Gijsbers R2, Van den Haute C1, Debyser Z2, Baekelandt V1; FK506 prevents neuroinflammation and dopaminergic neurodegeneration in an α-synuclein-based rat model for Parkinson’s disease. 2nd Leuven research Institute for Neurodegenerative Disorders (LIJD) seminar, December 17, 2012, Lamot, Mechelen, Belgium.
Baekelandt V. Development of an alpha-synuclein based rat model for Parkinson’s disease to test new therapeutic strategies. Invited lecture at ELAN Pharmaceuticals, San Francisco, CA, 8 June 2012.
Baekelandt V Unraveling the role of peptidyl prolyl isomerases in the aggregation and neurotoxicity of alpha-synuclein. Invited lecture in the framework of the Viikki biocenter lectures, Helsinki, Finland, March 19 2012.
Gerard M, Deleersnijder A, Van der Perren A, Van den Haute C, Debyser Z and Baekelandt V Validation of FKBP12 as modulator of α-synuclein aggregation and neurotoxicity. Society for Neuroscience meeting, Washington DC, 12-16 Nov 2011.
Van der Perren A, Van Rompuy A S, Toelen J, Casteels C, Gerard M, Vermaelen P, Bormans G, Van Laere K, Van den Haute C, Debyser Z, Baekelandt V. Therapeutic effect of FK506 in an optimized rAAV-based rat model for α-synucleinopathy. Society for Neuroscience meeting, Washington DC, 12-16 Nov 2011.
Deleersnijder A, Gerard M, Van Rompuy A S, Debyser Z and Baekelandt V Validation of FKBP12 as modulator of α-synuclein aggregation and neurotoxicity. 1st Leuven research Institute for Neurodegenerative Disorders (LIND) seminar, October 20, 2011, KU Leuven, Leuven, Belgium.
Poster Presentations
Van der Perren A, Toelen J, Van Rompuy A S, Casteels C, Sarre S, Gerard M, Maris M, Casadei N, Nuber S, Himmelreich U, Osorio Garcia M G, Reumers V, De Loor H, Kuypers D R J, Bormans G, Van Laere K, Gijsbers R, Van den Haute C, Debyser Z, Baekelandt V. FK506 decreases dopaminergic neurodegeneration and neuroinflammation in an optimized α-synuclein rat model for Parkinson’s disease. Society for Neuroscience meeting, New Orleans, LA, 13-17 Oct. 2012
Van der Perren A, Van Rompuy A S, Toelen J, Casteels C, Vermaelen P, Sarre S, Casadei N, Nuber S, Gerard M, Bormans G, Van Laere K, Van den Haute C, Debyser Z, Baekelandt V. Development of a robust alpha-synuclein-based rat model for Parkinson’s disease. Knowledge for Growth symposium of Flanders Bio, Ghent, May 24 2012.