TY  - JOUR
AU  - Mearelli, Marika
AU  - Hirschberg, Insa
AU  - Weissleder, Christin
AU  - Giachino, Carmela
AU  - Pérez, María José
AU  - Dubroux, Malvina
AU  - Provenzano, Francesca
AU  - Rizzuti, Mafalda
AU  - Ottoboni, Linda
AU  - Sheth, Udit
AU  - Gendron, Tania F
AU  - Corti, Stefania
AU  - Deleidi, Michela
TI  - C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC-Derived Microglia and Modulates Glial-Neuronal Crosstalk.
JO  - Glia
VL  - 74
IS  - 1
SN  - 0894-1491
CY  - Bognor Regis [u.a.]
PB  - Wiley-Liss
M1  - DZNE-2025-01331
SP  - e70080
PY  - 2026
AB  - 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.
KW  - Humans
KW  - C9orf72 Protein: genetics
KW  - C9orf72 Protein: metabolism
KW  - Microglia: metabolism
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Motor Neurons: metabolism
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Astrocytes: metabolism
KW  - DNA Repeat Expansion: genetics
KW  - Cells, Cultured
KW  - Cell Communication: physiology
KW  - Oxidative Stress
KW  - C9orf72 (Other)
KW  - amyotrophic lateral sclerosis/frontotemporal dementia (Other)
KW  - glial‐neuronal communication (Other)
KW  - immune system (Other)
KW  - induced pluripotent stem cells (Other)
KW  - microglia (Other)
KW  - C9orf72 Protein (NLM Chemicals)
KW  - C9orf72 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40888599
C2  - pmc:PMC12667002
DO  - DOI:10.1002/glia.70080
UR  - https://pub.dzne.de/record/282568
ER  -