Medium-Chain Fatty Acids, Beta-Hydroxybutyric Acid and Genetic Modulation of the Carnitine Shuttle Are Protective in a Drosophila Model of ALS Based on TDP-43
O'Conner, Abigail G.
Barrows, Jordan M.
Shreiner, Dakotah D.
Birchak, Gabriel J.
Zarnescu, Daniela C.
AffiliationUniv Arizona, Dept Mol & Cellular Biol
Univ Arizona, Dept Neurosci
Univ Arizona, Dept Neurol
amyotrophic lateral sclerosis
beta lipid oxidation
MetadataShow full item record
PublisherFRONTIERS MEDIA SA
CitationManzo E, O'Conner AG, Barrows JM, Shreiner DD, Birchak GJ and Zarnescu DC (2018) Medium-Chain Fatty Acids, Beta-Hydroxybutyric Acid and Genetic Modulation of the Carnitine Shuttle Are Protective in a Drosophila Model of ALS Based on TDP-43. Front. Mol. Neurosci. 11:182. doi: 10.3389/fnmol.2018.00182
Rights© 2018 Manzo, O'Conner, Barrows, Shreiner, Birchak and Zarnescu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).
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AbstractALS 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.
NoteOpen access journal.
VersionFinal published version
SponsorsNIH [T32GM008659, NS091299, MDA 418515]; HHMI Gilliam Fellowship for Advanced Studies; Undergraduate Biology Research Program; Beckman Foundation scholarship