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<p>Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disorder caused by expansion of a polyglutamine tract in the androgen receptor (AR). Here, we show that polyglutamine-expanded AR accumulates in the nucleus of motor neurons and induces aberrant upregulation of glutamatergic synaptic genes through dysfunction of the master transcriptional repressor REST during early postnatal development in a mouse model of SBMA (AR-97Q mice). Reducing mutant <i>AR</i> or restoring REST function using antisense oligonucleotides during the neonatal period attenuated the upregulation of glutamatergic synaptic genes and ameliorated the disease phenotype and histopathology in AR-97Q mice. Furthermore, we observed increased calcium activity in induced pluripotent stem cell-derived motor neurons from SBMA patients compared to those from healthy controls, reflecting neuronal hyperexcitability. Late-onset neurodegeneration in SBMA is attributable to early synaptic defects and the resulting hyperexcitability of motor neurons, which may represent therapeutic targets.</p>

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Restoring early postnatal synaptic dysregulation rescues motor neuron degeneration in a mouse model of Spinal and Bulbar Muscular Atrophy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月27日

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  • Tomoki Hirunagi,
  • Kentaro Sahashi,
  • Madoka Iida,
  • Kazunari Onodera,
  • Satoshi Yokoi,
  • Yosuke Ogura,
  • Genki Tohnai,
  • Kenji Sakakibara,
  • Kentaro Maeda,
  • C. Frank Bennett,
  • Yohei Okada,
  • Masahisa Katsuno

摘要

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disorder caused by expansion of a polyglutamine tract in the androgen receptor (AR). Here, we show that polyglutamine-expanded AR accumulates in the nucleus of motor neurons and induces aberrant upregulation of glutamatergic synaptic genes through dysfunction of the master transcriptional repressor REST during early postnatal development in a mouse model of SBMA (AR-97Q mice). Reducing mutant AR or restoring REST function using antisense oligonucleotides during the neonatal period attenuated the upregulation of glutamatergic synaptic genes and ameliorated the disease phenotype and histopathology in AR-97Q mice. Furthermore, we observed increased calcium activity in induced pluripotent stem cell-derived motor neurons from SBMA patients compared to those from healthy controls, reflecting neuronal hyperexcitability. Late-onset neurodegeneration in SBMA is attributable to early synaptic defects and the resulting hyperexcitability of motor neurons, which may represent therapeutic targets.