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

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

doi:10.1172/jci.insight.136539

Abstract

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.

Highlights

Spinal and bulbar muscular atrophy (SBMA) is an X-linked neuromuscular disorder characterized by lower motor neuron and skeletal muscle degeneration [1]
Through ChIP-seq and RNA sequencing (RNA-seq) experiments in SBMA iPSC-derived motor neurons (iMNs), we have shown that reduced histone H3K27 acetylation coincides with the repression of metabolic genes
These results are consistent with the well-known role of histone acetylation in regulating gene expression

Summary

Introduction

Spinal and bulbar muscular atrophy (SBMA) is an X-linked neuromuscular disorder characterized by lower motor neuron and skeletal muscle degeneration [1]. The signs of lower motor neuron disease include weakness, atrophy, and fasciculations in the bulbar and extremity muscles of SBMA patients [2]. It has been well established that transcriptional dysregulation in SBMA involves both a partial loss of the AR’s transactivation function [5] and a toxic gain of function of the mutant AR [6]. Previous studies have shown disruption of multiple cellular processes, including transcriptional dysregulation and impairment in mitochondrial function, as contributing to neuronal dysfunction in SBMA and other polyglutamine diseases [7, 8]

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Results

Conclusion