Abstract
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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by death of motor neurons
We tested the effect of blocking carnitine palmitoyl transferase 1 (CPT1), which previously has been shown to shift the metabolism from lipid- to glucose metabolism and show clinicalrelevant effects in a pilot study[24,25]
After we established that CPT1 lipid metabolism modulated the gut microbiome in superoxide dismutase 1 (SOD1) G93A mice, we investigated whether SOD1Cpt1a/Cpt1a mice had changes in their microbiome compared to SOD1 G93A mice at day 130, which could account for some of the differences seen in metabolic and inflammatory markers (Fig. 6)
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by death of motor neurons. We show that downregulating CPT1 shifts the gut microbiota communities towards a protective phenotype in SOD1 G93A mice These findings reveal that metabolism, and CPT1 lipid metabolism plays a central role in the SOD1 G93A mouse model and shows that CPT1 might be a therapeutic target in ALS. We report that modulation of CPT1 activity results in changes in the fecal gut microbiota, which is consistent with the increased recognition of the possible role of dysregulated microbiota in ALS and other neurodegenerative diseases These results suggest that the upregulated CPT1 lipid metabolism plays a critical role in the pathogenesis of the SOD1 G93A familiar form of ALS and that downregulation of CPT1 might be a potential target to restore the hyperactive metabolism
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