Dysregulation of metabolic pathways by carnitine palmitoyl-transferase 1 plays a key role in central nervous system disorders: experimental evidence based on animal models

Michael Sloth Trabjerg, Anne Skøttrup Mørkholt, Jacek Lichota, Michal Krystian Egelund Oklinski, Dennis Christian Andersen, Katrine Jønsson, Kasper Mørk, Marie Louise Nibelius Skjønnemand, Lona John Kroese, Colin Eliot Jason Pritchard, Ivo Johan Huijbers, Parisa Gazerani, Angelique Corthals, John Dirk Vestergaard Nieland*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

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.

Original languageEnglish
Article number15583
JournalScientific Reports
Volume10
Issue number1
Number of pages19
ISSN2045-2322
DOIs
Publication statusPublished - 2020

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