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
Author
Manzo, ErnestoO'Conner, Abigail G.
Barrows, Jordan M.
Shreiner, Dakotah D.
Birchak, Gabriel J.
Zarnescu, Daniela C.
Affiliation
Univ Arizona, Dept Mol & Cellular BiolUniv Arizona, Dept Neurosci
Univ Arizona, Dept Neurol
Issue Date
2018-05-31Keywords
TDP-43amyotrophic lateral sclerosis
metabolomics
lipid metabolism
beta lipid oxidation
carnitine shuttle
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FRONTIERS MEDIA SACitation
Manzo 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.2018.00182Rights
© 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).Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.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.Note
Open access journal.ISSN
1662-5099Version
Final published versionSponsors
NIH [T32GM008659, NS091299, MDA 418515]; HHMI Gilliam Fellowship for Advanced Studies; Undergraduate Biology Research Program; Beckman Foundation scholarshipAdditional Links
https://www.frontiersin.org/article/10.3389/fnmol.2018.00182/fullhttps://www.frontiersin.org/articles/10.3389/fnmol.2018.00182/supplementary-material/10.3389/fnmol.2018.00182.s001
ae974a485f413a2113503eed53cd6c53
10.3389/fnmol.2018.00182
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Except where otherwise noted, this item's license is described as © 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).