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

Michael Sloth Trabjerg; Dennis Christian Andersen; Pam Huntjens; Kasper Mørk; Nikolaj Warming; Ulla Bismark Kullab; Marie-Louise Nibelius Skjønnemand; Michal Krystian Oklinski; Kirsten Egelund Oklinski; Luise Bolther; Lona J Kroese; Colin E J Pritchard; Ivo J Huijbers; Angelique Corthals; Mads Toft Søndergaard; Henrik Bech Kjeldal; Cecilie Fjord Morre Pedersen; John Dirk Vestergaard Nieland

doi:10.1038/s41531-023-00450-y

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

NPJ Parkinsons Dis. 2023 Jan 21;9(1):6. doi: 10.1038/s41531-023-00450-y.

Authors

Michael Sloth Trabjerg¹, Dennis Christian Andersen¹, Pam Huntjens¹, Kasper Mørk¹, Nikolaj Warming¹, Ulla Bismark Kullab¹, Marie-Louise Nibelius Skjønnemand¹, Michal Krystian Oklinski¹, Kirsten Egelund Oklinski¹, Luise Bolther¹, Lona J Kroese², Colin E J Pritchard², Ivo J Huijbers², Angelique Corthals³, Mads Toft Søndergaard⁴, Henrik Bech Kjeldal⁴, Cecilie Fjord Morre Pedersen¹, John Dirk Vestergaard Nieland⁵

Affiliations

¹ Laboratory of Molecular Pharmacology, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.
² Mouse Clinic for Cancer and Aging (MCCA) Transgenic Facility, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
³ Department of Science, John Jay College of Criminal Justice, City University of New York, New York, NY, 10019, USA.
⁴ DNASense, Aalborg, Denmark.
⁵ Laboratory of Molecular Pharmacology, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark. Jdn@hst.aau.dk.

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.