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@ARTICLE{Mearelli:282568,
      author       = {Mearelli, Marika and Hirschberg, Insa and Weissleder,
                      Christin and Giachino, Carmela and Pérez, María José and
                      Dubroux, Malvina and Provenzano, Francesca and Rizzuti,
                      Mafalda and Ottoboni, Linda and Sheth, Udit and Gendron,
                      Tania F and Corti, Stefania and Deleidi, Michela},
      title        = {{C}9orf72 {R}epeat {E}xpansion {I}nduces {M}etabolic
                      {D}ysfunction in {H}uman i{PSC}-{D}erived {M}icroglia and
                      {M}odulates {G}lial-{N}euronal {C}rosstalk.},
      journal      = {Glia},
      volume       = {74},
      number       = {1},
      issn         = {0894-1491},
      address      = {Bognor Regis [u.a.]},
      publisher    = {Wiley-Liss},
      reportid     = {DZNE-2025-01331},
      pages        = {e70080},
      year         = {2026},
      abstract     = {The C9orf72 hexanucleotide repeat expansion mutation is the
                      most common genetic cause of amyotrophic lateral sclerosis
                      (ALS) and frontotemporal dementia, but its cell
                      type-specific effects on energy metabolism and immune
                      pathways remain poorly understood. Using induced pluripotent
                      stem cell (iPSC)-derived motor neurons, astrocytes, and
                      microglia from C9orf72 patients and their isogenic controls,
                      we investigated metabolic changes at the single-cell level
                      under basal and inflammatory conditions. Our results showed
                      that microglia are particularly susceptible to metabolic
                      disturbances. While C9orf72 motor neurons exhibited impaired
                      mitochondrial respiration and reduced ATP production,
                      C9orf72 microglia presented pronounced increases in
                      glycolytic activity and oxidative stress, accompanied by the
                      upregulation of the expression of key metabolic enzymes.
                      These metabolic changes in microglia were exacerbated by
                      inflammatory stimuli. To investigate how these changes
                      affect the broader cellular environment, we developed a
                      human iPSC-derived triculture system comprising motor
                      neurons, astrocytes, and microglia. This model revealed
                      increased metabolic activity in all cell types and
                      highlighted that microglia-driven metabolic reprogramming in
                      astrocytes contributes to the vulnerability of motor neurons
                      under inflammatory conditions. Our findings highlight the
                      central role of microglia in driving metabolic dysregulation
                      and intercellular crosstalk in ALS pathogenesis and suggest
                      that targeting metabolic pathways in immune cells may
                      provide new therapeutic avenues.},
      keywords     = {Humans / C9orf72 Protein: genetics / C9orf72 Protein:
                      metabolism / Microglia: metabolism / Induced Pluripotent
                      Stem Cells: metabolism / Motor Neurons: metabolism /
                      Amyotrophic Lateral Sclerosis: genetics / Amyotrophic
                      Lateral Sclerosis: metabolism / Astrocytes: metabolism / DNA
                      Repeat Expansion: genetics / Cells, Cultured / Cell
                      Communication: physiology / Oxidative Stress / C9orf72
                      (Other) / amyotrophic lateral sclerosis/frontotemporal
                      dementia (Other) / glial‐neuronal communication (Other) /
                      immune system (Other) / induced pluripotent stem cells
                      (Other) / microglia (Other) / C9orf72 Protein (NLM
                      Chemicals) / C9orf72 protein, human (NLM Chemicals)},
      cin          = {AG Deleidi},
      ddc          = {610},
      cid          = {I:(DE-2719)1210011},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40888599},
      pmc          = {pmc:PMC12667002},
      doi          = {10.1002/glia.70080},
      url          = {https://pub.dzne.de/record/282568},
}