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<p>Neurodegenerative disorders display brain region tropism accompanied by the emergence of distinct cellular states that contribute to disease pathogenesis, with molecular alterations occurring predominantly in glial cells. Here we show the emergence of a microglial state with distinct spatial distribution in the brains of terminally sick prion-infected mice characterized by high expression of Gpnmb (glycoprotein non-metastatic melanoma protein B), transcriptional signatures consistent with phagocytic activity, and increased expression of lysosomal genes in regions undergoing pronounced cell death. We find that this cellular state is not induced by pathological protein aggregates but by soluble factors released by dying cells regardless of the initiating insult. This work defines Gpnmb⁺ microglia as a&#xa0;distinct phagocytic state that links cell death to microglial activation and reveals a generalizable mechanism by which microglia respond to cell loss.</p>

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Gpnmb defines a phagocytic state of microglia linked to cell death in prion disease mouse model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月12日

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  • Davide Caredio,
  • Giovanni Mariutti,
  • Lisa Polzer,
  • Beatrice Gatta,
  • Martina Cerisoli,
  • Yasmine Laimeche,
  • Giulia Miracca,
  • Jeanne Droux,
  • Mohamad El Amki,
  • Marc Emmenegger,
  • Marian Hruska-Plochan,
  • Susanne Wegener,
  • Magdalini Polymenidou,
  • Matthias Schmitz,
  • Inga Zerr,
  • Elena De Cecco,
  • Adriano Aguzzi

摘要

Neurodegenerative disorders display brain region tropism accompanied by the emergence of distinct cellular states that contribute to disease pathogenesis, with molecular alterations occurring predominantly in glial cells. Here we show the emergence of a microglial state with distinct spatial distribution in the brains of terminally sick prion-infected mice characterized by high expression of Gpnmb (glycoprotein non-metastatic melanoma protein B), transcriptional signatures consistent with phagocytic activity, and increased expression of lysosomal genes in regions undergoing pronounced cell death. We find that this cellular state is not induced by pathological protein aggregates but by soluble factors released by dying cells regardless of the initiating insult. This work defines Gpnmb⁺ microglia as a distinct phagocytic state that links cell death to microglial activation and reveals a generalizable mechanism by which microglia respond to cell loss.