Metabolic dysregulation in ALS

Long-standing observations made in the clinic point to defects in metabolic regulation including abnormalities in glucose and lipid metabolism in ALS. Using our fruit fly model of ALS based on TDP-43 we have performed global metabolomics profiling and identified several significant metabolic changes consistent with alterations in cellular energetics. Specifically, increased pyruvate in both TDPWT and disease-associated TDPG298S models is suggestive of altered glucose metabolism. We also found increased tricarboxylic (TCA) cycle intermediates that just like pyruvate, are upregulated in plasma from ALS patients. Additionally, increased levels of fatty acid carnitine conjugates suggest decreased lipid beta-oxidation. Consistent with this observation, the ketone body marker 3-hydroxybutyrate (BHBA) is decreased, implying impaired mitochondrial lipid metabolism and an increased reliance on glycolysis for energy production in affected motor neurons. Based on these results and our previous published findings that antidiabetic drugs show partial effectiveness in ALS (see Drug discovery in Drosophila) we hypothesize that improving glucose and lipid metabolism through diet and genetic intervention can provide protection against neurodegeneration.

We have evidence that various dietary and genetic interventions aimed at increasing ATP production mitigate TDP-43 dependent locomotor dysfunction and increase lifespan. Transcriptional profiling data for key glycolytic enzymes are consistent with increased glycolysis in both fly and patient-derived iPS motor neurons. Together with genetic interaction experiments, data collected to date support the notion that increased glycolysis is a compensatory mechanism, perhaps a last resort for motor neurons to counter the well documented reduction in cellular ATP/dysfunctional mitochondrial metabolism caused by TDP-43 toxicity. Interestingly, these exciting findings tie in with recent reports that glycolytic enzymes cluster at synapses and, under stress conditions, regulate synaptic vesicle endocytosis, a process we found altered also through our studies on hsc70-4 mRNA translation. To determine whether increased reliance on glycolysis is specific to TDP-43 or represents a common mechanism, we are testing whether a high glucose diet improves locomotor function and increases lifespan in additional models of ALS, based on SOD1 and C9ORF72. So far we are finding that at least locomotor function is also improved in these other models by high glucose availability. We are continuing our “fly-to-man” approach to determine the contribution of glucose and lipid metabolism to ALS phenotypes and to establish the feasibility of pursuing therapeutic strategies aimed at restoring energy homeostasis.