Loeffler, J.-P. | bioRxiv Science

bioRxiv2022

Profound lipid dysregulation in mutant TDP-43 mice is ameliorated by the glucocerebrosidase 2 inhibitor ambroxol

The importance of dyslipidemia in amyotrophic lateral sclerosis (ALS) patients is increasingly recognised as a potential key mechanism driving disease onset, progression and survival. Evidence in familial ALS models suggests that lipid composition is significantly affected, however clinically relevant models have yet to be investigated. Using a powerful lipidomic approach, we uncover significant dysregulation of glycosphingolipid (GSL) metabolism in both the spinal cord and skeletal muscles of transgenic TDP-43Q331K mice. Treatment with the selective glucocerebrosidase 2 (GBA2) inhibitor ambroxol at symptom onset significantly improved motor and gait functions in TDP-43Q331K mice. Ambroxol treatment preserved motor neurons and neuromuscular junctions which was associated with modulation of GSL metabolism. Our study establishes significant lipid dysregulation in a clinically relevant model of ALS. Importantly, we show positive therapeutic outcomes in a mouse model of TDP-43 proteinopathy, suggesting that ambroxol may be a promising candidate to treat underlying dyslipidemia and symptoms of ALS.

neuroscience↗

bioRxiv2020

Altered skeletal muscle glucose-fatty acid flux in amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons, yet an increasing number of studies in both mouse models and patients with ALS suggest that altered metabolic homeostasis is a feature of disease. Pre-clinical and clinical studies have shown that modulation of energy balance can be beneficial in ALS. However, our capacity to target specific metabolic pathways or mechanisms requires detailed understanding of metabolic dysregulation in ALS. Here, using the SOD1G93A mouse model of ALS, we demonstrate that an increase in whole-body metabolism occurs at a time when glycolytic muscle exhibits an increased dependence on fatty acid oxidation. Using myotubes derived from muscle of ALS patients, we also show that increased dependence on fatty acid oxidation is associated with increased whole-body energy expenditure. In the present study, increased fatty acid oxidation was associated with slower disease progression. However, we observed considerable heterogeneity in whole-body metabolism and fuel oxidation profiles across our patient cohort. Thus, future studies that decipher specific metabolic changes at an individual patient level are essential for the development of treatments that aim to target metabolic pathways in ALS.

neuroscience↗