ePoster

TARGETING PGAM5-DRIVEN MITOCHONDRIAL INTEGRATED STRESS RESPONSE SLOWS ALS PROGRESSION ACROSS SUBTYPES

Xing Guoand 6 co-authors

Nanjing Medical University

FENS Forum 2026 (2026)

Barcelona, Spain

Board PS04-08PM-172

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Date TBA

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Board: PS04-08PM-172

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Poster Board

PS04-08PM-172

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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with diverse genetic and clinical subtypes, yet convergent pathogenic mechanisms remain poorly defined. A CRISPR-Cas9 screen identified PGAM5 as a common mediator of ALS pathogenesis. PGAM5 activates the mitochondrial integrated stress response (mtISR) via dephosphorylation of OMA1 at Ser223 and Ser237, thereby driving neuromuscular junction disruption and motor deficits. We show that PGAM5 is a substrate of VCP and is consistently elevated in spinal cords from sporadic ALS patients, in human spinal cord organoids derived from sporadic or familial ALS, and in ALS mouse models. Disruption of the PGAM5-OMA1 interaction by TAT-PO1, or pharmacological inhibition of PGAM5 with telmisartan, suppresses mtISR activation and ameliorates ALS-related phenotypes by reshaping mtISR outputs in a manner distinct from those elicited by eIF2B activation. These findings establish PGAM5 as a convergent and actionable therapeutic target across ALS subtypes.

Left side (healthy state): PGAM5 interacts with OMA1 on mitochondria to activate controlled mitochondrial integrated stress response (mtISR), sustaining neuromuscular junction and normal motor activity. As a VCP substrate, PGAM5 undergoes normal degradation. In contrast, the right side shows what goes wrong in both sporadic and familial ALS, reduced VCP solubility impairs PGAM5 degradation, casuing excessive PGAM5-mediated OMA1 dephosphorylation, which leads to abnormal mtISR, neuromuscular junction dysfunction and motor deficits. TAT-PO1 (disrupts PGAM5-OMA1 interaction) or telmisartan (pharmacologically inhibits PGAM5) suppresses mtISR and ameliorates ALS-related phenotypes by reshaping mtISR outputs.

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