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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

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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.

Original language	English
Article number	6
Journal	NPJ Parkinson's disease
Volume	9
Issue number	1
ISSN	2373-8057
DOIs	https://doi.org/10.1038/s41531-023-00450-y
Publication status	Published - 21 Jan 2023

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Trabjerg, M. S., Andersen, D. C., Huntjens, P., Mørk, K., Warming, N., Kullab, U. B., Skjønnemand, M.-L. N., Oklinski, M. K., Oklinski, K. E., Bolther, L., Kroese, L. J., Pritchard, C. E. J., Huijbers, I. J., Corthals, A., Søndergaard, M. T., Kjeldal, H. B., Pedersen, C. F. M., & Nieland, J. D. V. (2023). Inhibition of carnitine palmitoyl-transferase 1 is a potential target in a mouse model of Parkinson's disease. NPJ Parkinson's disease, 9(1), Article 6. https://doi.org/10.1038/s41531-023-00450-y

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title = "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.",

author = "Trabjerg, {Michael Sloth} and Andersen, {Dennis Christian} and Pam Huntjens and Kasper M{\o}rk and Nikolaj Warming and Kullab, {Ulla Bismark} and Skj{\o}nnemand, {Marie-Louise Nibelius} and Oklinski, {Michal Krystian} and Oklinski, {Kirsten Egelund} and Luise Bolther and Kroese, {Lona J} and Pritchard, {Colin E J} and Huijbers, {Ivo J} and Angelique Corthals and S{\o}ndergaard, {Mads Toft} and Kjeldal, {Henrik Bech} and Pedersen, {Cecilie Fjord Morre} and Nieland, {John Dirk Vestergaard}",

note = "{\textcopyright} 2023. The Author(s).",

year = "2023",

month = jan,

day = "21",

doi = "10.1038/s41531-023-00450-y",

language = "English",

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Trabjerg, MS, Andersen, DC, Huntjens, P, Mørk, K , Warming, N, Kullab, UB, Skjønnemand, M-LN, Oklinski, MK, Oklinski, KE, Bolther, L, Kroese, LJ, Pritchard, CEJ, Huijbers, IJ, Corthals, A, Søndergaard, MT , Kjeldal, HB, Pedersen, CFM & Nieland, JDV 2023, 'Inhibition of carnitine palmitoyl-transferase 1 is a potential target in a mouse model of Parkinson's disease', NPJ Parkinson's disease, vol. 9, no. 1, 6. https://doi.org/10.1038/s41531-023-00450-y

TY - JOUR

T1 - Inhibition of carnitine palmitoyl-transferase 1 is a potential target in a mouse model of Parkinson's disease

AU - Trabjerg, Michael Sloth

AU - Andersen, Dennis Christian

AU - Huntjens, Pam

AU - Mørk, Kasper

AU - Warming, Nikolaj

AU - Kullab, Ulla Bismark

AU - Skjønnemand, Marie-Louise Nibelius

AU - Oklinski, Michal Krystian

AU - Oklinski, Kirsten Egelund

AU - Bolther, Luise

AU - Kroese, Lona J

AU - Pritchard, Colin E J

AU - Huijbers, Ivo J

AU - Corthals, Angelique

AU - Søndergaard, Mads Toft

AU - Kjeldal, Henrik Bech

AU - Pedersen, Cecilie Fjord Morre

AU - Nieland, John Dirk Vestergaard

PY - 2023/1/21

Y1 - 2023/1/21

N2 - 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.

AB - 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.

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U2 - 10.1038/s41531-023-00450-y

DO - 10.1038/s41531-023-00450-y

M3 - Journal article

C2 - 36681683

SN - 2373-8057

VL - 9

JO - NPJ Parkinson's disease

JF - NPJ Parkinson's disease

IS - 1

M1 - 6

ER -

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

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