The contribution of metabolic dysfunction to genetic models of motor neuron disease

A growing body of literature underscores the presence of metabolic defects in Amyotrophic Lateral Sclerosis (ALS) patients and mouse models. A subpopulation of ALS patients possesses higher levels of resting energy expenditure and lower fat-free mass compared to healthy controls. Mutant superoxide dismutase1 (SOD1) mouse models of familial ALS (fALS) similarly possess hypermetabolic phenotypes. The pathophysiological relevance of these bioenergetic defects in ALS remains largely elusive. Adenosine monophospate-activated protein kinase (AMPK) and the adipocyte-derived hormone leptin are key regulators of energy homeostasis and thus might be dysregulated in various models of ALS. To investigate metabolic dysfunction, we utilized in vitro and in vivo genetic models of motor neuron disease engineered to express either human mutant SOD1 or TAR DNA-binding protein of 43 kDa molecular weight (TDP-43). We confirmed the presence of bioenergetic abnormalities by assessing cellular respiration and whole-animal metabolism and associate these with changes in AMPK and leptin activity. We then manipulated AMPK and leptin pathways, both pharmacologically and genetically, and investigated whether these pathways alter symptoms of motor neuron disease.;In this thesis work, we first report that AMPK and leptin signaling pathways are dysregulated in disease models and that dysregulation coincides with bioenergetic defects. Moreoever, reducing AMPK or leptin activity protects against disease progression. Attenuating AMPK or leptin activity in animal models improves motor performance and corrects metabolic defects. Second, we explore the contribution of individual tissues, such as neurons, muscle, and adipose tissue to disease. Although mutant SOD1 and TDP-43 induce degeneration specifically of motor neurons, we and others have observed that metabolic defects are present non-cell autonomously. Furthermore, the aforementioned metabolic manipulations may indirectly benefit degenerating neurons through non-neuronal tissues. Third, we identify several downstream targets and processes that are altered by reduced AMPK and leptin signaling and may be implicated in disease. Altogether, this body of work suggests that metabolic dysfunction is likely to be pathophysiologically relevant to motor neuron disease. Manipulating AMPK, leptin and other pathways that regulate energy homeostasis in genetic models of motor neuron disease may potentially be intriguing therapeutic targets to treat ALS patients.