TY - JOUR
T1 - Downregulating carnitine palmitoyl transferase 1 affects disease progression in the SOD1 G93A mouse model of ALS
AU - Trabjerg, Michael Sloth
AU - Andersen, Dennis Christian
AU - Huntjens, Pam
AU - Oklinski, Kirsten Egelund
AU - Bolther, Luise
AU - Hald, Jonas Laugård
AU - Baisgaard, Amalie Elton
AU - Mørk, Kasper
AU - Warming, Nikolaj
AU - Kullab, Ulla Bismark
AU - Kroese, Lona John
AU - Pritchard, Colin Eliot Jason
AU - Huijbers, Ivo Johan
AU - Nieland, John Dirk Vestergaard
PY - 2021/4/30
Y1 - 2021/4/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85105241112&partnerID=8YFLogxK
U2 - 10.1038/s42003-021-02034-z
DO - 10.1038/s42003-021-02034-z
M3 - Journal article
C2 - 33931719
SN - 2399-3642
VL - 4
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 509
ER -