Targeting PGAM5-driven mitochondrial integrated stress response slows ALS progression across subtypes - PubMed
a day ago
- #ALS
- #PGAM5
- #mtISR
- 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, leading to neuromuscular junction disruption and motor deficits.
- PGAM5 is elevated in ALS patients, organoids, and mouse models, and is a substrate of valosin-containing protein (VCP).
- Disrupting PGAM5-OMA1 interaction with TAT-PO1 or inhibiting PGAM5 with telmisartan suppresses mtISR activation and improves ALS-related phenotypes.
- PGAM5 is established as a convergent and actionable therapeutic target across ALS subtypes.