Scholarlink

<p>Microglia are the brain’s resident immune cells, essential for homeostasis and implicated in common neurodegenerative diseases like Alzheimer’s and Parkinson’s disease (PD), where their early activation and sustained inflammatory mediator release contribute to neuronal loss. However, their role in rare disorders is unclear. β-propeller protein-associated neurodegeneration (BPAN), caused by <i>WDR45</i> mutations, shares key features with PD, including iron accumulation and dopaminergic neuron loss, but the impact of microglia and mutant <i>WDR45</i> in BPAN pathophysiology remains unexplored. To address this, we established the first induced pluripotent stem stell (iPSC)-derived microglia model from BPAN patients. Parallel targeted transcriptomic and secretomic profiling revealed a shift from a homeostatic microglial toward a stress-adapted and transcriptionally reprogrammed state characterized by selective remodeling of immune signaling pathways and dysregulation of autophagy and cellular stress responses. Complementary secretomic analysis identified reduced secretion of lysosomal enzymes alongside increased shedding of immune-associated surface proteins, indicating altered lysosomal trafficking and remodeling of microglial immune signaling. These findings identify a distinct microglial phenotype in BPAN and implicate microglial dysfunction as a potential contributor to disease mechanisms, highlighting new avenues for therapeutic strategies targeting neuroimmune pathways.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Aberrant immunomodulatory signature in β-propeller protein-associated neurodegeneration patient iPSC-derived microglia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月15日

查看全文
  • Gamze Özata,
  • Rachel M. Wise,
  • Aida Cardona-Alberich,
  • Naiyareen F. Mayeen,
  • Stephan A. Müller,
  • Stefan F. Lichtenthaler,
  • Luigi Zecca,
  • Lena F. Burbulla

摘要

Microglia are the brain’s resident immune cells, essential for homeostasis and implicated in common neurodegenerative diseases like Alzheimer’s and Parkinson’s disease (PD), where their early activation and sustained inflammatory mediator release contribute to neuronal loss. However, their role in rare disorders is unclear. β-propeller protein-associated neurodegeneration (BPAN), caused by WDR45 mutations, shares key features with PD, including iron accumulation and dopaminergic neuron loss, but the impact of microglia and mutant WDR45 in BPAN pathophysiology remains unexplored. To address this, we established the first induced pluripotent stem stell (iPSC)-derived microglia model from BPAN patients. Parallel targeted transcriptomic and secretomic profiling revealed a shift from a homeostatic microglial toward a stress-adapted and transcriptionally reprogrammed state characterized by selective remodeling of immune signaling pathways and dysregulation of autophagy and cellular stress responses. Complementary secretomic analysis identified reduced secretion of lysosomal enzymes alongside increased shedding of immune-associated surface proteins, indicating altered lysosomal trafficking and remodeling of microglial immune signaling. These findings identify a distinct microglial phenotype in BPAN and implicate microglial dysfunction as a potential contributor to disease mechanisms, highlighting new avenues for therapeutic strategies targeting neuroimmune pathways.