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C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC-Derived Microglia and Modulates Glial-Neuronal
Marika Mearelli1,2, Insa Hirschberg1,2, Christin Weissleder3
1Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Glia
|September 1, 2025
Summary
The C9orf72 mutation disrupts cell metabolism in amyotrophic lateral sclerosis (ALS). Microglia show increased glycolytic activity and oxidative stress, impacting motor neuron vulnerability.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- The C9orf72 hexanucleotide repeat expansion is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.
- Cell type-specific metabolic and immune pathway effects of this mutation are not well understood.
Purpose of the Study:
- To investigate cell type-specific metabolic alterations in induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, and microglia from C9orf72 patients.
- To examine metabolic changes under basal and inflammatory conditions and their impact on intercellular communication.
Main Methods:
- Utilized iPSC-derived motor neurons, astrocytes, and microglia from C9orf72 patients and isogenic controls.
- Performed single-cell metabolic analysis under basal and inflammatory conditions.
- Developed a human iPSC-derived triculture system (motor neurons, astrocytes, microglia) to model intercellular effects.
Main Results:
- C9orf72 microglia exhibit heightened glycolytic activity, oxidative stress, and metabolic enzyme upregulation, unlike C9orf72 motor neurons with impaired mitochondrial respiration.
- Inflammatory stimuli exacerbate metabolic disturbances in C9orf72 microglia.
- Microglia-driven metabolic reprogramming in astrocytes contributes to motor neuron vulnerability in a triculture system.
Conclusions:
- Microglia play a central role in metabolic dysregulation and intercellular crosstalk in ALS pathogenesis.
- Targeting metabolic pathways in immune cells presents a potential therapeutic strategy for ALS.
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