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dc.contributor.authorManzo, Ernesto
dc.contributor.authorO'Conner, Abigail G.
dc.contributor.authorBarrows, Jordan M.
dc.contributor.authorShreiner, Dakotah D.
dc.contributor.authorBirchak, Gabriel J.
dc.contributor.authorZarnescu, Daniela C.
dc.date.accessioned2018-08-07T22:01:10Z
dc.date.available2018-08-07T22:01:10Z
dc.date.issued2018-05-31
dc.identifier.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.2018.00182en_US
dc.identifier.issn1662-5099
dc.identifier.doi10.3389/fnmol.2018.00182
dc.identifier.urihttp://hdl.handle.net/10150/628357
dc.description.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.en_US
dc.description.sponsorshipNIH [T32GM008659, NS091299, MDA 418515]; HHMI Gilliam Fellowship for Advanced Studies; Undergraduate Biology Research Program; Beckman Foundation scholarshipen_US
dc.language.isoenen_US
dc.publisherFRONTIERS MEDIA SAen_US
dc.relation.urlhttps://www.frontiersin.org/article/10.3389/fnmol.2018.00182/fullen_US
dc.relation.urlhttps://www.frontiersin.org/articles/10.3389/fnmol.2018.00182/supplementary-material/10.3389/fnmol.2018.00182.s001en_US
dc.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).en_US
dc.subjectTDP-43en_US
dc.subjectamyotrophic lateral sclerosisen_US
dc.subjectmetabolomicsen_US
dc.subjectlipid metabolismen_US
dc.subjectbeta lipid oxidationen_US
dc.subjectcarnitine shuttleen_US
dc.titleMedium-Chain Fatty Acids, Beta-Hydroxybutyric Acid and Genetic Modulation of the Carnitine Shuttle Are Protective in a Drosophila Model of ALS Based on TDP-43en_US
dc.typeArticleen_US
dc.contributor.departmentUniv Arizona, Dept Mol & Cellular Biolen_US
dc.contributor.departmentUniv Arizona, Dept Neuroscien_US
dc.contributor.departmentUniv Arizona, Dept Neurolen_US
dc.identifier.journalFRONTIERS IN MOLECULAR NEUROSCIENCEen_US
dc.description.noteOpen access journal.en_US
dc.description.collectioninformationThis 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.en_US
dc.eprint.versionFinal published versionen_US
dc.source.journaltitleFrontiers in Molecular Neuroscience
dc.source.volume11
refterms.dateFOA2018-08-07T22:01:11Z


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