Inhibition of carnitine palmitoyl-transferase 1 is a potential target in a mouse model of Parkinson’s disease

Abstract

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.

Mitochondria-Targeted Lipid Nanoparticles Loaded with Rotenone as a New Approach for the Treatment of Oncological Diseases

“…One such compound is rotenone (ROT), an isoflavonoid commonly used as a pesticide for animals, agricultural crops, and fisheries management [58]. It is known that ROT has the ability to inhibit the mitochondrial function of cells by inhibiting the mitochondrial complex Ⅰ, which is widely used to model Parkinson's disease in laboratory animals [59][60][61], as well as to study the role of the mitochondrial respiratory chain during apoptosis [62]. Some researchers have demonstrated the ROT effectiveness in triggering apoptosis of tumor cells through the production of reactive oxygen species in cells [63,64].…”