Bioenergetic deficits in Huntington’s disease iPSC-derived neural cells and rescue with glycolytic metabolites
Name
ddy430.pdf
Description
Published version
Size
8.06 MB
Format
Adobe PDF
Checksum (MD5)
63645c6ceba2aa3aae77da1ddfa17d2b
Author(s)
Kedaigle, Amanda J
Fraenkel, Ernest
Date Issued
March 7, 2019
Journal
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Citation
Kedaigle, Amanda J. et al. “Bioenergetic deficits in Huntington’s disease iPSC-derived neural cells and rescue with glycolytic metabolites.” Human Molecular Genetics 00 (2019): 1-15 © 2019 The Author(s)
Version
Final published version
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.
Subjects
Genetics(clinical)
Genetics
Molecular Biology
General Medicine
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Terms of Use
Creative Commons Attribution NonCommercial License 4.0
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1093/hmg/ddy430
