Journal Article

DZNE-2025-01331

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC-Derived Microglia and Modulates Glial-Neuronal Crosstalk.

Mearelli, M. (First author)DZNE* ; Hirschberg, I.DZNE* ; Weissleder, C.Extern* ; Giachino, C. ; Pérez, M. J.Extern* ; Dubroux, M. ; Provenzano, F.DZNE* ; Rizzuti, M. ; Ottoboni, L. ; Sheth, U. ; Gendron, T. F. ; Corti, S. ; Deleidi, M. (Last author)DZNE*

2026
Wiley-Liss Bognor Regis [u.a.]

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Please use a persistent id in citations: doi:10.1002/glia.70080

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.

Keyword(s): Humans (MeSH) ; C9orf72 Protein: genetics (MeSH) ; C9orf72 Protein: metabolism (MeSH) ; Microglia: metabolism (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Motor Neurons: metabolism (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Astrocytes: metabolism (MeSH) ; DNA Repeat Expansion: genetics (MeSH) ; Cells, Cultured (MeSH) ; Cell Communication: physiology (MeSH) ; Oxidative Stress (MeSH) ; C9orf72 ; amyotrophic lateral sclerosis/frontotemporal dementia ; glial‐neuronal communication ; immune system ; induced pluripotent stem cells ; microglia ; C9orf72 Protein ; C9orf72 protein, human

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Contributing Institute(s):

1. Mitochondria and Inflammation in Neurodegenerative Diseases (AG Deleidi)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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