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<p>Huntington’s disease (HD) is an incurable, neurodegenerative disorder. While the causative mutation – CAG expansions within the coding region of the Huntingtin (<i>HTT</i>) gene – has been identified over 30 years ago, the pathological mechanisms underlying HD are still not clear. The abnormal CAG track encodes a polyglutamine (polyQ) expanded protein, which leads to HTT protein misfolding. These polyQ aggregates can form insoluble inclusion bodies (IBs); however, whether IBs are protective or detrimental remains debatable. Here we developed fluorescent iPSC-based human neuronal models for polyQ-related disorders. Comparing cell death in IB+ and IB- iPSC-derived neurons, growing side-by-side, we demonstrate that polyQ IBs have a significant protective effect. Remarkably, knocking out <i>ATF3</i> prevented polyQ-IB formation and rendered the cells more vulnerable to induced stress. Taken together, our results reveal ATF3’s role in polyQ IB formation in human NPCs, and demonstrate that polyQ IBs protect cells from stress-induced death.</p>

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ATF3-dependent formation of inclusion bodies in polyQ-expressing human iPSC-derived neurons confers cellular protection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月2日

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  • Walaa Oweis,
  • Malka Nissim-Rafinia,
  • Elad Dvir,
  • Matan Sorek,
  • Sagiv Shifman,
  • Eran Meshorer

摘要

Huntington’s disease (HD) is an incurable, neurodegenerative disorder. While the causative mutation – CAG expansions within the coding region of the Huntingtin (HTT) gene – has been identified over 30 years ago, the pathological mechanisms underlying HD are still not clear. The abnormal CAG track encodes a polyglutamine (polyQ) expanded protein, which leads to HTT protein misfolding. These polyQ aggregates can form insoluble inclusion bodies (IBs); however, whether IBs are protective or detrimental remains debatable. Here we developed fluorescent iPSC-based human neuronal models for polyQ-related disorders. Comparing cell death in IB+ and IB- iPSC-derived neurons, growing side-by-side, we demonstrate that polyQ IBs have a significant protective effect. Remarkably, knocking out ATF3 prevented polyQ-IB formation and rendered the cells more vulnerable to induced stress. Taken together, our results reveal ATF3’s role in polyQ IB formation in human NPCs, and demonstrate that polyQ IBs protect cells from stress-induced death.