Dysregulation of mitochondrial bioenergetics, RNA processing, and cellular stress responses in FUS-ALS: a multi-dataset transcriptomic perspective.

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron (MN) degeneration. Mutations in the FUS gene, particularly the aggressive P525L variant, disrupt nuclear localization of the FUS RNA-binding protein, resulting in cytoplasmic accumulation, altered RNA metabolism, and toxic aggregation. Astrocytes also contribute to disease progression through non-cell-autonomous mechanisms.

Objective: To identify shared and cell-type-specific molecular mechanisms underlying FUS-associated ALS through integrated transcriptomic analysis of human induced pluripotent stem cell (hiPSC)-derived motor neurons and astrocytes.

Methods: Five publicly available RNA-sequencing datasets from hiPSC-derived motor neurons and astrocytes carrying FUS mutations were analyzed. Differential gene expression and Gene Ontology enrichment analyses were performed to identify dysregulated genes and pathways.

Results: Both cell types showed convergent dysregulation of mitochondrial/bioenergetic pathways (oxidative phosphorylation, ATP metabolism, translation, membrane potential). Pathway analysis across motor neuron datasets identified largely MN-specific enrichment in cell-cycle regulation, intracellular trafficking, and stimulus response, while only four pathways were shared with astrocytes, most notably NADH dehydrogenase complex assembly, enriched across all datasets and both cell types, marking mitochondrial complex I as the strongest convergent signature. RNA processing/splicing pathways were also enriched, consistent with FUS function. Shared DEGs included upregulated COMT, TXNRD2, and PCDHGB4, and downregulated PCDH17 and C11orf87, implicating neurotransmitter metabolism, antioxidant defenses, and adhesion. Stress pathways (oxidative stress, autophagy, heat-shock, ER stress/UPR) were broadly altered, with UPR genes mainly upregulated and inflammatory genes downregulated.

Conclusion: FUS-ALS involves shared mitochondrial complex I and stress-response disturbances layered onto MN-intrinsic cell-cycle and trafficking dysregulation, reflecting convergent and cell-type-specific mechanisms.