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C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC ‐Derived Microglia and Modulates Glial‐Neuronal Crosstalk
Marika Mearelli, Insa Hirschberg, Christin Weissleder, Carmela Giachino, Maria Jose Perez J., Malvina Dubroux, Francesca Provenzano, Mafalda Rizzuti et al.. Glia, 2025-09-01
Topic: Brain proteins, microglia and lab models
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.
Key findings
- Our results showed that microglia are particularly susceptible to metabolic disturbances.
- 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.
Why it matters
In cell models from C9orf72 patients, microglia showed metabolic disturbances and oxidative stress that worsened with inflammation, and a three-cell culture system suggested microglia-driven changes in astrocytes make motor neurons more vulnerable. This is early laboratory work on ALS and frontotemporal dementia, not a treatment or cure for Alzheimer's disease.
Study details
- Evidence strengthLow
How this study scored 39/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Glia) |
| Journal's citation record | 2 / 4 | Glia: journal h-index 233 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “ipsc”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 1 / 7 | Cited 3 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 1.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 3 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Michela Deleidi: h-index 33 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Inserm: institution h-index 1,988 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 9 institution(s) in 4 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40888599) |
| Free to read | 2 / 2 | Free to read |
| Total | 39 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Mearelli, M., Hirschberg, I., Weissleder, C., Giachino, C., Maria Jose Perez, J., Dubroux, M., et al. (2025). C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC ‐Derived Microglia and Modulates Glial‐Neuronal Crosstalk. Glia. https://doi.org/10.1002/glia.70080
Vancouver
Mearelli M, Hirschberg I, Weissleder C, Giachino C, Maria Jose Perez J, Dubroux M, et al. C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC ‐Derived Microglia and Modulates Glial‐Neuronal Crosstalk. Glia. 2025. doi:10.1002/glia.70080. PMID: 40888599.
BibTeX
@article{mearelli2025-40888599,
author = {Mearelli, Marika and Hirschberg, Insa and Weissleder, Christin and Giachino, Carmela and Maria Jose Perez, J. and Dubroux, Malvina and Provenzano, Francesca and Rizzuti, Mafalda and others},
title = {{C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC ‐Derived Microglia and Modulates Glial‐Neuronal Crosstalk}},
journal = {Glia},
year = {2025},
doi = {10.1002/glia.70080},
pmid = {40888599},
url = {https://doi.org/10.1002/glia.70080}
}
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here.