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Abstract: FR-PO729

Targeting Axoneme Polyglutamylation as a Potential Therapeutic Approach for ADPKD Treatment

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Author

  • He, Kai, Mayo Clinic, Rochester, Minnesota, United States
Background

ADPKD is the most common inherited renal disorders mainly caused by mutations of PKD1 or PKD2, which encodes Polycystin 1 (PC1) and Polycystin 2 (PC2) respectively. PC1 and PC2 co-localize to the primary cilium of kidney epithelial cells and have been proposed to form a receptor/channel complex to sense environmental cues. Recently, the structural mapping of ADPKD pathological mutations indicates that the pathogenic mechanism of PKD mutations are mainly associate with the incorrect folding or trafficking of PC1/PC2 complex. Thus, theoretically, correcting the proper cilia localization of PC1/PC2 complex could restore its functional dosage and holds strong potential for being developed as a therapeutic avenue to delay or even prevent the renal cystogenesis. However, perusing this strategy is impeded by the lack of understanding of how the ciliary targeting/maintenance of polycystins are controlled. Polyglutamylation is one of the tubulin posttranslational modifications (PTMs) that occur predominantly on cilia axoneme. We recently discovered a novel paradigm that axoneme polyglutamylation is essential for the ciliary anchoring of polycystins, indicative of its potential for being used as a drug target.

Methods

1. Imaging-based drug screen.
2. Immunofluorescent.
3. 3D culture.
4. Embryonic kindney culture.

Results

Here, by implementing axoneme polyglutamylation as readout, we performed an imaging-based small molecule screen and discovered several hits that can increase PC2 dosage and restore the ciliary localization of PC2 in PKD cell model by promoting axoneme hyperglutamylation. Mechanistically, these drugs strongly promote the ciliary trafficking of TTLL5 and TTLL6, the key tubulin polyglutamylases that localize to primary cilia. We also have pinpointed the real molecular target of identified hits for inducing axoneme hyperglutamylation, which is overexpressed in ADPKD patients. Remarkably, inhibition of the identified molecular target by its selective inhibitor significantly suppressed the cyst growth in in vitro and ex in vivo models of renal cystogenesis, suggesting its strong potential for being developed as drug target for ADPKD treatment.

Conclusion

Targeting axoneme ployglutamylation could be a effective way to restore the functional levels of polycystins and hold a strong potential for being developed as a therapeutic approach for ADPKD.

Funding

  • NIDDK Support