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

Communications biology 2021 Apr 30

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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.

Citation

Michael Sloth Trabjerg, Dennis Christian Andersen, Pam Huntjens, Kirsten Egelund Oklinski, Luise Bolther, Jonas Laugård Hald, Amalie Elton Baisgaard, Kasper Mørk, Nikolaj Warming, Ulla Bismark Kullab, Lona John Kroese, Colin Eliot Jason Pritchard, Ivo Johan Huijbers, John Dirk Vestergaard Nieland. Downregulating carnitine palmitoyl transferase 1 affects disease progression in the SOD1 G93A mouse model of ALS. Communications biology. 2021 Apr 30;4(1):509