A common mediator ALS pathogenesis across subtypes identified!

Fatal neurodegenerative disorder, amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons (MNs) but is genetically and clinically heterogeneous, although convergent pathogenic mechanisms is not well understood.

The researchers in this study identified phosphoglycerate mutase-5 (PGAM5) as a common mediator of ALS pathogenesis. PGAM5 activates the mitochondrial integrated stress response (mtISR) via dephosphorylation of metallopeptidase OMA1, thereby driving neuromuscular junction disruption and motor deficits.

PGAM5 is elevated in spinal cords from sporadic ALS patients, in human spinal cord organoids derived from sporadic or familial ALS, and in ALS mouse models.

The authors show that PGAM5 is a substrate of valosin-containing protein (VCP) and disruption of PGAM5- OMA1 interaction or PGAM5

inhibition suppresses mtISR activation and ameliorates ALS-related phenotypes.

https://www.cell.com/neuron/fulltext/S0896-6273(26)00086-3

https://sciencemission.com/PGAM5-driven-mitochondrial-integrated-stress-response