Hypoxic stress is an early pathogenic event in human VCP-mutant ALS astrocytes
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Hannah Franklin Hamish Crerar Venkata Nishita Mohan Parnandi Michael Lattke Stanislaw Majewski Ben Clarke Husayn Pallikonda Michael Howell Simon Boulton Rickie PataniAbstract
Astrocytes are essential regulators of neuronal health, and their dysfunction contributes to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Using human induced pluripotent stem cell (iPSC)-derived astrocytes carrying ALS-associated VCP mutations, we uncover cell-autonomous activation of the hypoxia response under basal conditions. VCP-mutant astrocytes exhibit increased nuclear hypoxia-inducible factor (HIF)-1ɑ, mitochondrial depolarization, and lipid droplet accumulation. Mimicking hypoxia in control astrocytes by HIF-1ɑ stabilization with dimethyloxalylglycine recapitulates these phenotypes. Transcriptomic and CUT&RUN profiling reveal direct HIF-1ɑ binding to canonical hypoxia-responsive genes in VCP-mutant astrocytes and a transcriptional signature of metabolic reprogramming and mitochondrial dysfunction under normoxia. Furthermore, conditioned medium from hypoxia-exposed astrocytes fails to rescue RNA-binding protein mislocalization in motor neurons, unlike medium from healthy counterparts. Together, these findings demonstrate that aberrant HIF-1ɑ activation drives astrocytic dysfunction and compromises neuronal support, identifying hypoxic stress as an early and functionally consequential event in VCP-mutant ALS, with therapeutic implications for targeting HIF-1ɑ signaling.
Journal details
Journal
Stem Cell Reports
Volume
21
Issue number
1
Pages
102723
Available online
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Publisher website (DOI)
10.1016/j.stemcr.2025.102723
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Europe PubMed Central
41349534
Pubmed
41349534
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