Glucose metabolism is dysregulated in Parkinson’s disease (PD) causing a shift toward the metabolism of lipids. Carnitine palmitoyl-transferase 1A (CPT1A) regulates the key step in the metabolism of long-chain fatty acids. The aim of this study is to evaluate the effect of downregulating CPT1, either genetically with a Cpt1a P479L mutation or medicinally on PD using chronic rotenone mouse models using C57Bl/6J and Park2 knockout mice. We show that Cpt1a P479L mutant mice are resistant to rotenone-induced PD, and that inhibition of CPT1 is capable of restoring neurological function, normal glucose metabolism, and alleviate markers of PD in the midbrain. Furthermore, we show that downregulation of lipid metabolism via CPT1 alleviates pathological motor and non-motor behavior, oxidative stress, and disrupted glucose homeostasis in Park2 knockout mice. Finally, we confirm that rotenone induces gut dysbiosis in C57Bl/6J and, for the first time, in Park2 knockout mice. We show that this dysbiosis is alleviated by the downregulation of the lipid metabolism via CPT1.

葡萄糖代谢在帕金森病 (PD) 中失调，导致向脂质代谢转变。肉碱棕榈酰转移酶 1A (CPT1A) 调节长链脂肪酸代谢的关键步骤。本研究的目的是使用慢性鱼藤酮小鼠模型使用 C57Bl/6J 和Park2基因敲除小鼠评估下调 CPT1 的效果，无论是遗传上的Cpt1a P479L 突变还是医学上的。我们表明Cpt1aP479L 突变小鼠对鱼藤酮诱导的 PD 具有抵抗力，抑制 CPT1 能够恢复神经功能、正常葡萄糖代谢并减轻中脑 PD 标志物。此外，我们表明，通过 CPT1 下调脂质代谢可减轻Park2基因敲除小鼠的病理性运动和非运动行为、氧化应激和葡萄糖稳态破坏。最后，我们证实鱼藤酮在 C57Bl/6J 中诱导肠道生态失调，并且首次在Park2基因敲除小鼠中诱导。我们表明，通过 CPT1 下调脂质代谢可以缓解这种生态失调。