TY - JOUR
T1 - Linking epigenetic dysregulation, mitochondrial impairment, and metabolic dysfunction in SBMA motor neurons
AU - Pourshafie, Naemeh
AU - Masati, Ester
AU - Bunker, Eric
AU - Nickolls, Alec R.
AU - Thepmankorn, Parisorn
AU - Johnson, Kory
AU - Feng, Xia
AU - Ekins, Tyler
AU - Grunseich, Christopher
AU - Fischbeck, Kenneth H.
N1 - Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/7/9
Y1 - 2020/7/9
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.136539
DO - 10.1172/jci.insight.136539
M3 - Article
C2 - 32641584
AN - SCOPUS:85087714744
SN - 2379-3708
VL - 5
JO - JCI Insight
JF - JCI Insight
IS - 13
M1 - e136539
ER -