Trabjerg Michael Sloth, Andersen Dennis Christian, Huntjens Pam, Mørk Kasper, Warming Nikolaj, Kullab Ulla Bismark, Skjønnemand Marie-Louise Nibelius, Oklinski Michal Krystian, Oklinski Kirsten Egelund, Bolther Luise, Kroese Lona J, Pritchard Colin E J, Huijbers Ivo J, Corthals Angelique, Søndergaard Mads Toft, Kjeldal Henrik Bech, Pedersen Cecilie Fjord Morre, Nieland John Dirk Vestergaard
Laboratory of Molecular Pharmacology, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.
Mouse Clinic for Cancer and Aging (MCCA) Transgenic Facility, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
NPJ Parkinsons Dis. 2023 Jan 21;9(1):6. doi: 10.1038/s41531-023-00450-y.
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.
帕金森病（PD）中葡萄糖代谢失调，导致代谢向脂质代谢转变。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C57Bl/6J和Park2基因敲除小鼠的慢性鱼藤酮小鼠模型，评估通过Cpt1a P479L突变进行基因下调CPT1或药物下调CPT1对PD的影响。我们发现Cpt1a P479L突变小鼠对鱼藤酮诱导的PD具有抗性，并且抑制CPT1能够恢复神经功能、正常葡萄糖代谢，并减轻中脑中PD的标志物。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、氧化应激以及破坏的葡萄糖稳态。最后，我们证实鱼藤酮在C57Bl/6J小鼠以及首次在Park2基因敲除小鼠中诱导肠道微生物群失调。我们表明通过CPT1下调脂质代谢可减轻这种失调。
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