Targeting PGAM5-driven mitochondrial integrated stress response slows ALS progression across subtypes

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) presents significant genetic and clinical heterogeneity, complicating the understanding of its underlying pathogenic mechanisms.
• Convergent molecular pathways mediating ALS pathogenesis remain poorly defined, hindering the development of broad-spectrum therapies.

Purpose of the Study:

• To identify common molecular mediators of amyotrophic lateral sclerosis (ALS) pathogenesis.
• To investigate the role of phosphoglycerate mutase-5 (PGAM5) in ALS and its potential as a therapeutic target.

Main Methods:

• Utilized CRISPR-Cas9 screening to identify key proteins in ALS pathogenesis.
• Investigated the interaction between PGAM5 and metallopeptidase OMA1, including phosphorylation sites.
• Assessed PGAM5 levels in patient samples, organoids, and animal models.
• Employed selective inhibitors (TAT-PO1) and pharmacological agents (telmisartan) to modulate PGAM5 activity.

Main Results:

• Phosphoglycerate mutase-5 (PGAM5) was identified as a common mediator of ALS pathogenesis.
• PGAM5 activates the mitochondrial integrated stress response (mtISR) by dephosphorylating OMA1, leading to neuromuscular junction disruption and motor deficits.
• PGAM5 levels are elevated in sporadic ALS patients, ALS organoids, and ALS mouse models.
• Inhibition of the PGAM5-OMA1 interaction or PGAM5 itself suppressed mtISR activation and ameliorated ALS phenotypes.

Conclusions:

• PGAM5 acts as a convergent and actionable therapeutic target in amyotrophic lateral sclerosis (ALS).
• Targeting PGAM5 offers a potential strategy to address the diverse subtypes of ALS by modulating the mitochondrial integrated stress response.