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<p>Caspase-3, a cysteine-aspartic protease canonically known for its role in apoptotic cell death, has been implicated in several non-apoptotic functions, particularly in microglia, the brain-resident macrophages. These novel functions appear to depend on distinct levels of caspase-3 activation; however, the role of basal caspase-3 activity remains unclear. Here, we show that basal caspase-3 regulates RNA splicing in microglia, and its deficiency in a Parkinson´s disease (PD) model leads to splicing dysregulation. Loss of basal caspase-3 activity also increases double-stranded RNA (dsRNA) accumulation, inducing a type I interferon response. Additionally, caspase-3 deficiency impairs mitochondrial respiration, reduces ATP production, and causes sex-specific mitochondrial abnormalities, predominantly in female microglia. Together, our findings uncover a non-apoptotic, homeostatic role for basal caspase-3 activity in microglia. Its disruption, such as in PD, may drive key molecular features of neuroinflammation and neurodegeneration, positioning caspase-3 as a critical regulator of microglial function in health and disease.</p>

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Caspase-3 regulates RNA splicing and mitochondrial dynamics in microglia during Parkinson’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月4日

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  • Rafael Medina-Guzmán,
  • Bazhena Bahatyrevich-Kharitonik,
  • Marie-Kim St-Pierre,
  • Sara Márquez-Pérez,
  • Elena Gavilán,
  • Cristóbal Coronel-Guisado,
  • Alicia Flores-Cortes,
  • Rodrigo García-Valiente,
  • Sandro Argüelles,
  • Edel Kavanagh,
  • Yiyi Yang,
  • Tomas Deierborg,
  • José Luis Venero,
  • Cristina González-Aguilera,
  • Bertrand Joseph,
  • Miguel Ángel Burguillos

摘要

Caspase-3, a cysteine-aspartic protease canonically known for its role in apoptotic cell death, has been implicated in several non-apoptotic functions, particularly in microglia, the brain-resident macrophages. These novel functions appear to depend on distinct levels of caspase-3 activation; however, the role of basal caspase-3 activity remains unclear. Here, we show that basal caspase-3 regulates RNA splicing in microglia, and its deficiency in a Parkinson´s disease (PD) model leads to splicing dysregulation. Loss of basal caspase-3 activity also increases double-stranded RNA (dsRNA) accumulation, inducing a type I interferon response. Additionally, caspase-3 deficiency impairs mitochondrial respiration, reduces ATP production, and causes sex-specific mitochondrial abnormalities, predominantly in female microglia. Together, our findings uncover a non-apoptotic, homeostatic role for basal caspase-3 activity in microglia. Its disruption, such as in PD, may drive key molecular features of neuroinflammation and neurodegeneration, positioning caspase-3 as a critical regulator of microglial function in health and disease.