Abstract
ALS patients exhibit dyslipidemia, hypermetabolism and weight loss; in addition, cellular energetics deficits have been detected prior to denervation. Although evidence that metabolism is altered in ALS is compelling, the mechanisms underlying metabolic dysregulation and the contribution of altered metabolic pathways to disease remain poorly understood. Here we use a Drosophila model of ALS based on TDP-43 that recapitulates hallmark features of the disease including locomotor dysfunction and reduced lifespan. We performed a global, unbiased metabolomic profiling of larvae expressing TDP-43 (wild-type, TDPWT or disease-associated mutant, TDPG298S) and identified several lipid metabolism associated alterations. Among these, we found a significant increase in carnitine conjugated long-chain fatty acids and a significant decrease in carnitine, acetyl-carnitine and beta-hydroxybutyrate, a ketone precursor. Taken together these data suggest a deficit in the function of the carnitine shuttle and reduced lipid beta oxidation. To test this possibility we used a combined genetic and dietary approach in Drosophila. Our findings indicate that components of the carnitine shuttle are misexpressed in the context of TDP-43 proteinopathy and that genetic modulation of CPT1 or CPT2 expression, two core components of the carnitine shuttle, mitigates TDP-43 dependent locomotor dysfunction, in a variant dependent manner. In addition, feeding medium-chain fatty acids or beta-hydroxybutyrate improves locomotor function, consistent with the notion that bypassing the carnitine shuttle deficit is neuroprotective. Taken together, our findings highlight the potential contribution of the carnitine shuttle and lipid beta oxidation in ALS and suggest strategies for therapeutic intervention based on restoring lipid metabolism in motor neurons.
Highlights
Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease characterized by upper and lower motor neuron atrophy
Whole larvae expressing TAR DNA binding protein 43 (TDP-43) in motor neurons with the D42 GAL4 driver were analyzed by Metabolon, Inc. using ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) and gas chromatography-mass spectroscopy (GC-MS)
Among the 133 compounds associated with lipid metabolism that were detected by the Metabolon platform, we found 21 metabolites significantly altered in the context of TDP-43 human wild type (TDPWT) (P < 0.05) and 31 altered in the context of TDPG298S (P < 0.05)
Summary
Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease characterized by upper and lower motor neuron atrophy. One of the pathological hallmarks of disease is the accumulation of the TAR DNA binding protein 43 (TDP-43) in cytoplasmic aggregates, both in glial and neuronal cells (Neumann et al, 2006) These aggregates have been identified in 97% of all ALS, and 45% of frontotemporal degeneration (FTD) cases making it an important, unifying feature of the ALS/FTD spectrum disorder (Ling et al, 2013). Metabolic profiling data from ALS patients show significantly altered metabolites consistent with defects in cellular energetics (Lawton et al, 2012, 2014). These findings highlight the need for identifying metabolic alterations at the cellular level, in motor neurons and glia, that may uncover key strategies for preventing and ameliorating metabolic dysregulation in ALS
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