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000282568 1001_ $$0P:(DE-2719)9001388$$aMearelli, Marika$$b0$$eFirst author$$udzne
000282568 245__ $$aC9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC-Derived Microglia and Modulates Glial-Neuronal Crosstalk.
000282568 260__ $$aBognor Regis [u.a.]$$bWiley-Liss$$c2026
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000282568 520__ $$aThe 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.
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000282568 650_7 $$2Other$$aC9orf72
000282568 650_7 $$2Other$$aamyotrophic lateral sclerosis/frontotemporal dementia
000282568 650_7 $$2Other$$aglial‐neuronal communication
000282568 650_7 $$2Other$$aimmune system
000282568 650_7 $$2Other$$ainduced pluripotent stem cells
000282568 650_7 $$2Other$$amicroglia
000282568 650_7 $$2NLM Chemicals$$aC9orf72 Protein
000282568 650_7 $$2NLM Chemicals$$aC9orf72 protein, human
000282568 650_2 $$2MeSH$$aHumans
000282568 650_2 $$2MeSH$$aC9orf72 Protein: genetics
000282568 650_2 $$2MeSH$$aC9orf72 Protein: metabolism
000282568 650_2 $$2MeSH$$aMicroglia: metabolism
000282568 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000282568 650_2 $$2MeSH$$aMotor Neurons: metabolism
000282568 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000282568 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000282568 650_2 $$2MeSH$$aAstrocytes: metabolism
000282568 650_2 $$2MeSH$$aDNA Repeat Expansion: genetics
000282568 650_2 $$2MeSH$$aCells, Cultured
000282568 650_2 $$2MeSH$$aCell Communication: physiology
000282568 650_2 $$2MeSH$$aOxidative Stress
000282568 7001_ $$0P:(DE-2719)9001983$$aHirschberg, Insa$$b1$$udzne
000282568 7001_ $$0P:(DE-2719)9001801$$aWeissleder, Christin$$b2$$udzne
000282568 7001_ $$aGiachino, Carmela$$b3
000282568 7001_ $$0P:(DE-2719)9001465$$aPérez, María José$$b4$$udzne
000282568 7001_ $$aDubroux, Malvina$$b5
000282568 7001_ $$0P:(DE-2719)9000707$$aProvenzano, Francesca$$b6$$udzne
000282568 7001_ $$aRizzuti, Mafalda$$b7
000282568 7001_ $$aOttoboni, Linda$$b8
000282568 7001_ $$00000-0003-4360-7892$$aSheth, Udit$$b9
000282568 7001_ $$aGendron, Tania F$$b10
000282568 7001_ $$aCorti, Stefania$$b11
000282568 7001_ $$0P:(DE-2719)2810385$$aDeleidi, Michela$$b12$$eLast author
000282568 773__ $$0PERI:(DE-600)1474828-9$$a10.1002/glia.70080$$gVol. 74, no. 1, p. e70080$$n1$$pe70080$$tGlia$$v74$$x0894-1491$$y2026
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