Bioenergetic deficits in Huntington’s disease iPSC-derived neural cells and rescue with glycolytic metabolites

Amanda J. Kedaigle, Ernest Fraenkel, Ranjit S. Atwal, Min Wu, James F. Gusella, Marcy E. MacDonald, Julia A. Kaye, Steven Finkbeiner, Virginia B. Mattis, Colton M. Tom, Clive Svendsen, Alvin R. King, Yumay Chen, Jennifer T. Stocksdale, Ryan G. Lim, Malcolm Casale, Ping H. Wang, Leslie M. Thompson, Sergey S. Akimov, Tamara RatovitskiNicolas Arbez, Christopher A. Ross

Research output: Contribution to journalArticlepeer-review

Abstract

Altered cellular metabolism is believed to be an important contributor to pathogenesis of the neurodegenerative disorder Huntington’s disease (HD). Research has primarily focused on mitochondrial toxicity, which can cause death of the vulnerable striatal neurons, but other aspects of metabolism have also been implicated. Most previous studies have been carried out using postmortem human brain or non-human cells. Here, we studied bioenergetics in an induced pluripotent stem cell-based model of the disease. We found decreased adenosine triphosphate (ATP) levels in HD cells compared to controls across differentiation stages and protocols. Proteomics data and multiomics network analysis revealed normal or increased levels of mitochondrial messages and proteins, but lowered expression of glycolytic enzymes. Metabolic experiments showed decreased spare glycolytic capacity in HD neurons, while maximal and spare respiratory capacities driven by oxidative phosphorylation were largely unchanged. ATP levels in HD neurons could be rescued with addition of pyruvate or late glycolytic metabolites, but not earlier glycolytic metabolites, suggesting a role for glycolytic deficits as part of the metabolic disturbance in HD neurons. Pyruvate or other related metabolic supplements could have therapeutic benefit in HD.

Original languageEnglish (US)
Pages (from-to)1757-1771
Number of pages15
JournalHuman molecular genetics
Volume29
Issue number11
DOIs
StatePublished - 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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