Towards Repurposing FK506 for the treatment of Parkinson's Disease

The goal of this project is to delineate potential biomarkers as a surrogate for calcineurin activity and hence efficacy of low doses of FK506 through an in vivo approach using α-syn transgenic mice. In rodents, subcutaneous injection of FK506 yields great brain penetrance with a long lasting effect in brain and rapid clearance from the blood, avoiding any potential side effects (Unpublished data, Figure 2A). Importantly, we found that this excellent brain penetrance resulted in the ability of low doses of FK506 to protect against neurodegeneration caused by α-syn in a rat model of PD (Unpublished data, Figure 2B). We have previously established that the activation of the transcription factor NFAT by calcineurin drives toxicity in response to α- syn6 (Figure 1). Among NFAT’s transcriptional targets are inflammatory cytokines as well as the insulin growth factor 1 (IGF-1)7,8. Using another well characterized rodent model of PD9, we have begun to explore whether neuroinflammation and IGF-1 are upregulated in these mice and whether these are responsive to treatment with low doses of FK506. Preliminary data indicates that low doses of FK506 can indeed reduce the neuroinflammatory phenotype observed in these mice as well as the expression levels of IGF-1 in the brain (unpublished data, Figure 2C,D).