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Citation
Manzo, E., Lorenzini, I., Barrameda, D., O'Conner, A.G., Barrows, J.M., Starr, A., Kovalik, T., Rabichow, B.E., Lehmkuhl, E.M., Shreiner, D.D., Joardar, A., Liévens, J.C., Bowser, R., Sattler, R., Zarnescu, D.C. (2019). Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS.  eLife 8(): e45114.
FlyBase ID
FBrf0242626
Publication Type
Research paper
Abstract

Amyotrophic Lateral Sclerosis (ALS), is a fatal neurodegenerative disorder, with TDP-43 inclusions as a major pathological hallmark. Using a Drosophila model of TDP-43 proteinopathy we found significant alterations in glucose metabolism including increased pyruvate, suggesting that modulating glycolysis may be neuroprotective. Indeed, a high sugar diet improves locomotor and lifespan defects caused by TDP-43 proteinopathy in motor neurons or glia, but not muscle, suggesting that metabolic dysregulation occurs in the nervous system. Overexpressing human glucose transporter GLUT-3 in motor neurons mitigates TDP-43 dependent defects in synaptic vesicle recycling and improves locomotion. Furthermore, PFK mRNA, a key indicator of glycolysis, is upregulated in flies and patient derived iPSC motor neurons with TDP-43 pathology. Surprisingly, PFK overexpression rescues TDP-43 induced locomotor deficits. These findings from multiple ALS models show that mechanistically, glycolysis is upregulated in degenerating motor neurons as a compensatory mechanism and suggest that increased glucose availability is protective.

PubMed ID
PubMed Central ID
PMC6557627 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    eLife
    Title
    eLife
    ISBN/ISSN
    2050-084X
    Data From Reference