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<p>Aging is a major risk factor in amyotrophic lateral sclerosis (ALS) and other adult-onset neurodegenerative disorders. Whereas young neurons are capable of buffering disease-causing stresses, mature neurons lose this ability and degenerate over time. We hypothesized that the resilience of young motor neurons could be restored by reexpression of the embryonic motor neuron selector transcription factors ISL1 and LHX3. We found that viral reexpression of ISL1 and LHX3 selectively in postnatal motor neurons reactivates aspects of their youthful gene expression program and alleviates key disease-relevant phenotypes in the SOD1<sup>G93A</sup> mouse model of ALS. Our results suggest that redeployment of lineage-specific neuronal selector transcription factors can be an effective strategy to attenuate age-dependent phenotypes in neurodegenerative disease.</p>

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Embryonic motor neuron programming factors reactivate immature gene expression and suppress ALS pathologies in postnatal motor neurons

  • 期刊论文

  • 发表日期：

    2025年8月12日

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  • Emily R. Lowry,
  • Tulsi Patel,
  • Jonathon A. Costa,
  • Elizabeth Chang,
  • Shahroz Tariq,
  • Hranush Melikyan,
  • Ian Davis,
  • Siaresh Aziz,
  • Georgia Ntermentzaki,
  • Francesco Lotti,
  • Hynek Wichterle

摘要

Aging is a major risk factor in amyotrophic lateral sclerosis (ALS) and other adult-onset neurodegenerative disorders. Whereas young neurons are capable of buffering disease-causing stresses, mature neurons lose this ability and degenerate over time. We hypothesized that the resilience of young motor neurons could be restored by reexpression of the embryonic motor neuron selector transcription factors ISL1 and LHX3. We found that viral reexpression of ISL1 and LHX3 selectively in postnatal motor neurons reactivates aspects of their youthful gene expression program and alleviates key disease-relevant phenotypes in the SOD1G93A mouse model of ALS. Our results suggest that redeployment of lineage-specific neuronal selector transcription factors can be an effective strategy to attenuate age-dependent phenotypes in neurodegenerative disease.