TY - JOUR
T1 - Dysregulation of metabolic pathways by carnitine palmitoyl-transferase 1 plays a key role in central nervous system disorders
T2 - experimental evidence based on animal models
AU - Trabjerg, Michael Sloth
AU - Mørkholt, Anne Skøttrup
AU - Lichota, Jacek
AU - Oklinski, Michal Krystian Egelund
AU - Andersen, Dennis Christian
AU - Jønsson, Katrine
AU - Mørk, Kasper
AU - Skjønnemand, Marie Louise Nibelius
AU - Kroese, Lona John
AU - Pritchard, Colin Eliot Jason
AU - Huijbers, Ivo Johan
AU - Gazerani, Parisa
AU - Corthals, Angelique
AU - Nieland, John Dirk Vestergaard
PY - 2020
Y1 - 2020
N2 - The etiology of CNS diseases including multiple sclerosis, Parkinson’s disease and amyotrophic lateral sclerosis remains elusive despite decades of research resulting in treatments with only symptomatic effects. In this study, we provide evidence that a metabolic shift from glucose to lipid is a key mechanism in neurodegeneration. We show that, by downregulating the metabolism of lipids through the key molecule carnitine palmitoyl transferase 1 (CPT1), it is possible to reverse or slowdown disease progression in experimental models of autoimmune encephalomyelitis-, SOD1G93A and rotenone models, mimicking these CNS diseases in humans. The effect was seen both when applying a CPT1 blocker or by using a Cpt1a P479L mutant mouse strain. Furthermore, we show that diet, epigenetics, and microbiota are key elements in this metabolic shift. Finally, we present a systemic model for understanding the complex etiology of neurodegeneration and how different regulatory systems are interconnected through a central metabolic pathway that becomes deregulated under specific conditions.
AB - The etiology of CNS diseases including multiple sclerosis, Parkinson’s disease and amyotrophic lateral sclerosis remains elusive despite decades of research resulting in treatments with only symptomatic effects. In this study, we provide evidence that a metabolic shift from glucose to lipid is a key mechanism in neurodegeneration. We show that, by downregulating the metabolism of lipids through the key molecule carnitine palmitoyl transferase 1 (CPT1), it is possible to reverse or slowdown disease progression in experimental models of autoimmune encephalomyelitis-, SOD1G93A and rotenone models, mimicking these CNS diseases in humans. The effect was seen both when applying a CPT1 blocker or by using a Cpt1a P479L mutant mouse strain. Furthermore, we show that diet, epigenetics, and microbiota are key elements in this metabolic shift. Finally, we present a systemic model for understanding the complex etiology of neurodegeneration and how different regulatory systems are interconnected through a central metabolic pathway that becomes deregulated under specific conditions.
U2 - 10.1038/s41598-020-72638-8
DO - 10.1038/s41598-020-72638-8
M3 - Journal article
C2 - 32973137
AN - SCOPUS:85091456201
SN - 2045-2322
VL - 10
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 15583
ER -