Muscone promotes remyelination and alleviates Parkinson’s disease by targeting FKBP5 in MPTP-induced mouse model

INTRODUCTION: The side effects and limited efficacy of existing dopaminergic treatments for Parkinson's disease (PD) underscore the urgent need for novel therapeutic strategies. Promoting myelin renewal might be one promising avenue. However, therapies targeting remyelination for PD treatment remain to be explored. OBJECTIVES: This study aimed to evaluate the therapeutic efficacy of the natural compound muscone (Mus) on PD pathology and symptoms, and to elucidate its underlying mechanisms. METHODS: Using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine -induced PD model, we evaluated the therapeutic effect of Mus and investigated its pro-myelination mechanism through transcriptomic analysis of the substantia nigra. The feasibility of attenuating parkinsonian neurodegeneration through enhancing remyelination was confirmed using the pro-myelinating agent clemastine. The key protein that Mus targets to improve remyelination was identified combining molecular docking, the surface plasmon resonance assay, and pharmacological blockade both in vitro and in vivo, with the downstream mechanisms elucidated in oligodendrocyte lineage cells. RESULTS: Mus rescued neuronal degeneration as well as motor and non-motor symptoms in PD mice, with the novel mechanism involving supporting oligodendrocyte progenitor cells survival and differentiation to enhance remyelination. Pharmacological blockade of FK506 binding protein 5 (FKBP5) negated the pro-myelination effect and therapeutic efficacy in Mus-treated PD mice, indicating that Mus protected against PD primarily through FKBP5-dependent remyelination. Mechanistically, Mus directly targeted FKBP5 to activate the AKT-FoxO3 pathway in the context of PD, thereby elevating myelin basic protein expression in oligodendrocyte lineage cells. CONCLUSION: Our study highlights the great prospect of Mus as a novel therapeutic agent against PD by regulating FKBP5-AKT-FoxO3 signaling pathway and proposes facilitating remyelination as a promising avenue for PD intervention.