Undocking of an extensive ciliary network induces proteostasis and cell fate switching resulting in severe primary ciliary dyskinesia.

Summary

This mechanistic study shows that CCDC39/CCDC40 variants disrupt docking of the multiciliary network, triggering proteostasis stress and cell fate switching in multiciliated airway cells, offering an explanation for severe primary ciliary dyskinesia beyond motility loss. The work reframes PCD as a ciliopathy involving structural-network failure and proteostatic responses.

Key Findings

• CCDC39/CCDC40 variants cause undocking of the multiciliary network in human multiciliated cells.
• Proteostasis stress responses are activated, linking structural failure to cellular dysfunction.
• Cell fate switching accompanies ciliary network disruption, explaining severe PCD beyond motility loss.

Clinical Implications

Clinicians should consider that severe PCD phenotypes may reflect proteostasis and epithelial cell fate alterations; biomarkers of proteotoxic stress and imaging of ciliary network integrity could refine diagnosis and stratification.

Limitations

• Abstract indicates cellular systems; in vivo validation and longitudinal patient data are not detailed
• Quantitative prevalence and generalizability across PCD genotypes require further study

Future Directions

Validate proteostasis biomarkers in patient cohorts, test modulators of ciliary anchoring and proteostasis as therapeutic candidates, and map timelines of fate switching in airway epithelium in vivo.