Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis

Abstract

Metabolic dysfunction is an important modulator of disease course in amyotrophic lateral sclerosis (ALS). We report here that a familial mouse model (transgenic mice over-expressing the G93A mutation of the Cu/Zn superoxide dismutase 1 gene) of ALS enters a progressive state of acidosis that is associated with several metabolic (hormonal) alternations that favor lipolysis. Extensive investigation of the major determinants of H + concentration (i.e., the strong ion difference and the strong ion gap) suggests that acidosis is also due in part to the presence of an unknown anion. Consistent with a compensatory response to avert pathological acidosis, ALS mice harbor increased accumulation of glycogen in CNS and visceral tissues. The altered glycogen is associated with fluctuations in lysosomal and neutral α-glucosidase activities. Disease-related changes in glycogen, glucose, and α-glucosidase activity are also found in spinal cord tissue samples of autopsied patients with ALS. Collectively, these data provide insights into the pathogenesis of ALS as well as potential targets for drug development.

“Preconditioning” with latrepirdine, an adenosine 5′-monophosphate-activated protein kinase activator, delays amyotrophic lateral sclerosis progression in SOD1G93A mice

“…This is in accordance with a previously published study that documented increased AMPK activation at PND 90 in these mice (Lim et al 2012, Perera et al 2014. These data may mechanistically link AMPK activation with previously published bioenergetic abnormalities described in this mouse model (Dodge et al 2013, Kim et al 2011a, Fergani et al 2007, Dupuis et al 2004.…”

“…Furthermore, SOD1 G93A and SOD1 G86R mice show a decrease in body weight and fat mass during disease progression, reduced levels of circulating triglycerides, and evidence of increased lipolysis (Dodge et al 2013, Kim et al 2011a, Fergani et al 2007, Dupuis et al 2004. ALS patients also exhibit higher resting levels of energy expenditure, weight loss, a hypermetabolic phenotype and increased lipolysis (Kasarskis et al 1996, Desport et al 2005, Dupuis et al 2008, Bouteloup et al 2009, Funalot et al 2009, Dodge et al 2013. Hence, there is growing evidence for decreased glucose utilisation and metabolic re-programming in…”

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

“…Similar to our previous work (23,50), our present study underscores in metabolic terms that multiple pathological aspects of ALS are still unexplored. A greater understanding of the biological pathways that regulate Cer flux following inhibition of GCS in ALS mice has the potential to lead to the identification of toxic entities that are targetable for drug development.…”

MicroRNA regulators of cholinergic signaling link neuromuscular, cardiac and metabolic systems

“…Aside from motor neuron degeneration, ALS is associated with several defects in energy metabolism (65,66,67,68), and a better metabolism correlates with longer survival of ALS patients (69,70,71). Alongside other metabolic features, augmenting glucose intolerance is considered a sign of deteriorating and dysregulated metabolic homeostasis progressing along with the disease (66,72).…”