Linking epigenetic dysregulation, mitochondrial impairment, and metabolic dysfunction in SBMA motor neurons

Naemeh Pourshafie, Ester Masati, Eric Bunker, Alec R. Nickolls, Parisorn Thepmankorn, Kory Johnson, Xia Feng, Tyler Ekins, Christopher Grunseich, Kenneth H. Fischbeck

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by a polyglutamine expansion in the androgen receptor (AR). Using gene expression analysis and ChIP sequencing, we mapped transcriptional changes in genetically engineered patient stem cell–derived motor neurons. We found that transcriptional dysregulation in SBMA can occur through AR-mediated histone modification. We detected reduced histone acetylation, along with decreased expression of genes encoding compensatory metabolic proteins and reduced substrate availability for mitochondrial function. Furthermore, we found that pyruvate supplementation corrected this deficiency and improved mitochondrial function and SBMA motor neuron viability. We propose that epigenetic dysregulation of metabolic genes contributes to reduced mitochondrial ATP production. Our results show a molecular link between altered epigenetic regulation and mitochondrial metabolism that contributes to neurodegeneration.

Original languageEnglish (US)
Article numbere136539
JournalJCI Insight
Issue number13
StatePublished - Jul 9 2020

ASJC Scopus subject areas

  • General Medicine

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