Abstract
Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine‐mediated neuromuscular disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. While transcriptional dysregulation is known to play a critical role in the pathogenesis of SBMA, the underlying molecular pathomechanisms remain unclear. DNA methylation is a fundamental epigenetic modification that silences the transcription of various genes that have a CpG‐rich promoter. Here, we showed that DNA methyltransferase 1 (Dnmt1) is highly expressed in the spinal motor neurons of an SBMA mouse model and in patients with SBMA. Both genetic Dnmt1 depletion and treatment with RG108, a DNA methylation inhibitor, ameliorated the viability of SBMA model cells. Furthermore, a continuous intracerebroventricular injection of RG108 mitigated the phenotype of SBMA mice. DNA methylation array analysis identified hairy and enhancer of split 5 (Hes5) as having a CpG island with hyper‐methylation in the promoter region, and the Hes5 expression was strongly silenced in SBMA. Moreover, Hes5 over‐expression rescued the SBMA cells possibly by inducing Smad2 phosphorylation. Our findings suggest DNA hyper‐methylation underlies the neurodegeneration in SBMA.
Highlights
Spinal and bulbar muscular atrophy (SBMA) is a polyglutaminemediated neuromuscular disease caused by a CAG repeat expansion in the androgen receptor (AR) gene
While Dnmt3a and Dnmt3b were mainly stained in the cytoplasm of the motor neurons in wild-type, AR-24Q, and AR with 97 CAG repeat sequences (AR-97Q) mouse spinal cords, DNA methyltransferase 1 (Dnmt1) immunoreactivity was enriched in the nucleus of spinal motor neurons in SBMA model mice (Fig 1D and E)
Immunofluorescence staining verified the colocalization of Dnmt1 with 1C2, an abnormal polyglutamine marker, in the spinal motor neurons of SBMA mice; this phenomenon was observed in 85.7% of neurons (Fig 1F)
Summary
Spinal and bulbar muscular atrophy (SBMA) is a polyglutaminemediated neuromuscular disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. DNA methylation is a fundamental epigenetic modification that silences the transcription of various genes that have a CpG-rich promoter. We showed that DNA methyltransferase 1 (Dnmt1) is highly expressed in the spinal motor neurons of an SBMA mouse model and in patients with SBMA. Both genetic Dnmt depletion and treatment with RG108, a DNA methylation inhibitor, ameliorated the viability of SBMA model cells. DNA methylation array analysis identified hairy and enhancer of split 5 (Hes5) as having a CpG island with hyper-methylation in the promoter region, and the Hes expression was strongly silenced in SBMA. Our findings suggest DNA hyper-methylation underlies the neurodegeneration in SBMA
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