Downregulating carnitine palmitoyl transferase 1 affects disease progression in the SOD1 G93A mouse model of ALS

• Published in: Communications biology 2021-04, Vol.4 (1), p.509-509, Article 509
• Main Authors: Trabjerg, Michael Sloth, Andersen, Dennis Christian, Huntjens, Pam, Oklinski, Kirsten Egelund, Bolther, Luise, Hald, Jonas Laugård, Baisgaard, Amalie Elton, Mørk, Kasper, Warming, Nikolaj, Kullab, Ulla Bismark, Kroese, Lona John, Pritchard, Colin Eliot Jason, Huijbers, Ivo Johan, Nieland, John Dirk Vestergaard
• Format: Article
• Language: English
• Subjects: 13/51; 38/39; 38/91; 631/154; 631/337; 64/110; 692/617/375/1917/1285; 692/617/375/364; 82/80; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Biology; Biomedical and Life Sciences; Carnitine; Carnitine O-Palmitoyltransferase - antagonists & inhibitors; Cell death; Corticosterone; Disease Models, Animal; Disease Progression; Down-Regulation; Enzyme Inhibitors - pharmacology; Epoxy Compounds - pharmacology; Etiology; Female; Gastrointestinal Microbiome; High fat diet; Inflammation; Intestinal microflora; Life Sciences; Lipid metabolism; Lipids; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiota; Mimicry; Mitochondria; Motor neuron diseases; Motor neurone disease; Mutation; Oxidative stress; Phenotypes; Superoxide dismutase; Superoxide Dismutase-1 - physiology; Therapeutic applications; Therapeutic targets
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-021-02034-z

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by death of motor neurons. The etiology and pathogenesis remains elusive despite decades of intensive research. Herein, we report that dysregulated metabolism plays a central role in the SOD1 G93A mouse model mimicking ALS. Specifically, we report that the activity of carnitine palmitoyl transferase 1 (CPT1) lipid metabolism is associated with disease progression. Downregulation of CPT1 activity by pharmacological and genetic methods results in amelioration of disease symptoms, inflammation, oxidative stress and mitochondrial function, whereas upregulation by high-fat diet or corticosterone results in a more aggressive disease progression. Finally, we show that downregulating CPT1 shifts the gut microbiota communities towards a protective phenotype in SOD1 G93A mice. These findings reveal that metabolism, and specifically CPT1 lipid metabolism plays a central role in the SOD1 G93A mouse model and shows that CPT1 might be a therapeutic target in ALS. Trabjerg et al. show that the activity of carnitine palmitoyl transferase 1 (CPT1) and lipid metabolism are associated with the disease progression of the SOD1 G93A mouse model mimicking a motor neuron disease Amyotrophic lateral sclerosis (ALS). This study suggests CPT1 as a potential therapeutic target in treating ALS.