Abstract
Spinal and bulbar muscular atrophy (SBMA) results from a CAG repeat expansion within the androgen receptor gene (AR). It is unclear why motor neurons selectively degenerate and there are currently no treatments for this debilitating disease. To uncover the causative genes and pathways involved in motor neuron dysfunction, we undertook transcriptomic profiling of primary embryonic motor neurons from SBMA mice. We show that transcriptional dysregulation occurs early during development in SBMA motor neurons. One gene found to be dysregulated, Chmp7, was also altered in vivo in spinal cord before symptom onset in SBMA mice, and crucially in motor neuron precursor cells derived from SBMA patient stem cells, suggesting that Chmp7 may play a causal role in disease pathogenesis by disrupting the endosome-lysosome system. Furthermore, genes were enriched in SBMA motor neurons in several key pathways including p53, DNA repair, WNT and mitochondrial function. SBMA embryonic motor neurons also displayed dysfunctional mitochondria along with DNA damage, possibly resulting from DNA repair gene dysregulation and/or mitochondrial dysfunction. This indicates that a coordinated dysregulation of multiple pathways leads to development of SBMA. Importantly, our findings suggest that the identified pathways and genes, in particular Chmp7, may serve as potential therapeutic targets in SBMA.
Highlights
Spinal and bulbar muscular atrophy (SBMA), known as Kennedy’s Disease, is a slowly progressive, adult onset neuromuscular disease, which primarily affects males
To characterise early transcriptional dysregulation and establish disease mechanisms in SBMA, we first performed a global transcriptomic screen of purified cultured spinal cord motor neurons from embryonic AR100 and wild-type (WT) mice treated with dihydrotestosterone (DHT), to reflect the ligand dependency of the disease (Fig. 1A–C)
We found that 178 genes were upregulated, whilst 287 genes were significantly downregulated in AR100 motor neurons compared with WT cultures (Supplementary Information, Fig. S1A–C and Tables S1, S2)
Summary
First exon of the androgen receptor (AR) gene[3]. The polymorphic CAG repeat normally ranges from 9–36, while patients possess greater than 37 repeats. There is a clear neurogenic contribution to the motor dysfunction observed in mice, suggesting the polyQ-expanded AR in motor neurons causes secondary pathology in muscle and is required for the development of the full range of symptoms[12]. We found that the polyQ expansion in the AR results in transcriptional dysregulation which occurs very early in development and is present even in embryonic motor neurons from SBMA mice. Chmp[7], which plays a role in autophagic flux and the endosome-lysosome system as part of the ESCRT-III complex, was altered in the analysis performed on embryonic motor neurons, as well as in adult mice in vivo, before symptom onset in the two primary sites of pathology, both in laser captured spinal cord motor neurons and hindlimb muscle, indicating the potential importance of this gene in disease pathogenesis. The identified pathways and genes, Chmp[7], may represent attractive molecular targets for development of a therapeutic approach for SBMA
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