Rapamycin exerts neuroprotective effects by inhibiting FKBP12 instead of mTORC1 in the mouse model of Parkinson's disease

Abstract

Parkinson's disease (PD), characterized by the selective loss of nigral dopaminergic neurons, is a common neurodegenerative disorder for which effective disease-modifying therapies remain unavailable. Rapamycin, a clinical immunosuppressant used for decades, has demonstrated neuroprotective effects in various animal models of neurological diseases, including PD. These effects are believed to be mediated through the inhibition of mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling, with rapamycin binding to FKBP12. However, recent studies have suggested that mTOR activation can be neuroprotective in degenerating dopaminergic neurons, presenting a paradox to the neuroprotective mechanism of rapamycin via mTORC1 inhibition. In this study, we showed that mTORC1 signaling was inactivated in nigral dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Notably, the optimal neuroprotective dose of rapamycin did not inhibit mTORC1 signaling nor restore autophagy defects in nigral dopaminergic neurons of MPTP-treated male C57BL/6 mice. Furthermore, acute Raptor knockout in dopaminergic neurons, which abolishes mTORC1 activity, did not diminish rapamycin's neuroprotective effects, suggesting that its protection is independent of mTORC1 inhibition. Importantly, rapamycin is also a potent inhibitor of FKBP12, a peptidyl-prolyl cis-trans isomerase highly expressed in the brain. Selective knockdown of FKBP12 in nigral dopaminergic neurons confers neuroprotective effects comparable to that of rapamycin, with no synergism observed when the two are combined. Collectively, our results indicate that rapamycin exerts neuroprotective effects in parkinsonian mice through inhibition of FKBP12 rather than mTORC1 signaling. These findings suggest that FKBP12 may serve as a novel target for disease-modifying therapies in PD.