Defective autophagy in GNE myopathy is rescued by inhibition of noncanonical Akt-mTORC1 activation across multiple isogenic models - PubMed
8 hours ago
- #autophagy
- #GNE myopathy
- #AKT-mTORC1 pathway
- GNE myopathy is an autosomal recessive disease caused by mutations in the GNE gene, leading to impaired sialic acid biosynthesis and rimmed vacuoles.
- Transcriptome analysis on GNE myoblast models identified autophagy-related gene sets as key pathogenic signatures.
- The study reveals that aberrant activation of the noncanonical AKT-mTORC1 pathway, driven by excessive extracellular matrix production, inhibits autophagy via ULK1 phosphorylation.
- A transcriptome-based drug screen nominated copanlisib, an FDA-approved PI3K inhibitor, as a potential therapeutic candidate.
- Functional validation showed that copanlisib reactivates autophagy in human pluripotent stem cell-derived neuromuscular organoids by restoring ULK1 activity.