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.