Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS

Ernesto Manzo, Ileana Lorenzini, Dianne Barrameda, Abigail G. O'Conner, Jordan M. Barrows, Alexander Starr, Tina Kovalik, Benjamin E. Rabichow, Erik M. Lehmkuhl, Dakotah D. Shreiner, Archi Joardar, Jean Charles Liévens, Robert Bowser, Rita Sattler, Daniela C Zarnescu

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
JournaleLife
Volume8
DOIs
StatePublished - Jun 10 2019

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Keywords

  • D. melanogaster
  • drosophila
  • human
  • iPSC
  • neuroscience

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

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. https://doi.org/10.7554/eLife.45114