Eupatilin rescues ciliary transition zone defects to ameliorate ciliopathy-related phenotypes
Yong Joon Kim, … , Ho Jeong Kwon, Joon Kim
Yong Joon Kim, … , Ho Jeong Kwon, Joon Kim
Published July 23, 2018
Citation Information: J Clin Invest. 2018;128(8):3642-3648. https://doi.org/10.1172/JCI99232.
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Concise Communication Development Ophthalmology

Eupatilin rescues ciliary transition zone defects to ameliorate ciliopathy-related phenotypes

Abstract

Ciliopathies are clinically overlapping genetic disorders involving structural and functional abnormalities of cilia. Currently, there are no small-molecule drugs available to treat ciliary defects in ciliopathies. Our phenotype-based screen identified the flavonoid eupatilin and its analogs as lead compounds for developing ciliopathy medication. CEP290, a gene mutated in several ciliopathies, encodes a protein that forms a complex with NPHP5 to support the function of the ciliary transition zone. Eupatilin relieved ciliogenesis and ciliary receptor delivery defects resulting from deletion of CEP290. In rd16 mice harboring a blinding Cep290 in-frame deletion, eupatilin treatment improved both opsin transport to the photoreceptor outer segment and electrophysiological responses of the retina to light stimulation. The rescue effect was due to eupatilin-mediated inhibition of calmodulin binding to NPHP5, which promoted NPHP5 recruitment to the ciliary base. Our results suggest that deficiency of a ciliopathy protein could be mitigated by small-molecule compounds that target other ciliary components that interact with the ciliopathy protein.

Authors

Yong Joon Kim, Sungsoo Kim, Yooju Jung, Eunji Jung, Ho Jeong Kwon, Joon Kim

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Figure 2

Eupatilin promotes Smo-EGFP transport to the ciliary membrane.

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Eupatilin promotes Smo-EGFP transport to the ciliary membrane. (A) Fluor...
(A) Fluorescence micrographs visualizing ciliary Smo-EGFP intensity in CEP290WT and CEP290null RPE1 cells. (B) Quantification (arbitrary unit) of the experiment presented in A. (C) Effect of cytoD and eupatilin on ciliary Smo-EGFP intensity and cilium elongation in CEP290null RPE1 cells. Cells were treated with the indicated chemicals for 48 hours in the absence of serum. (D and E) Quantification (arbitrary unit) of the experiment presented in C. Scale bars indicate 5 μm. Error bars represent SEM (30–60 cells of each condition from 2 independent experiments were analyzed; **P <0.01, t test).