Linking epigenetic dysregulation, mitochondrial impairment, and metabolic dysfunction in SBMA motor neurons.
Epigenetics
Genetics
Mitochondria
Neurological disorders
Neuroscience
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
09 07 2020
09 07 2020
Historique:
received:
16
01
2020
accepted:
21
05
2020
entrez:
10
7
2020
pubmed:
10
7
2020
medline:
10
6
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32641584
pii: 136539
doi: 10.1172/jci.insight.136539
pmc: PMC7406250
doi:
pii:
Substances chimiques
AR protein, human
0
Peptides
0
Receptors, Androgen
0
polyglutamine
26700-71-0
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
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