Cholesterol in the ciliary membrane as a therapeutic target of polycystic kidney

Primary cilia are non-motile, microtubule-based cellular protrusions that sense extracellular chemical and mechanical cues, converting them into intracellular signals. Ciliary dysfunction causes ciliopathies including polycystic kidney disease and retinal degeneration. The ciliary membrane is highly enriched in cholesterol, which is essential for the physiological function of ciliary-localized receptors, including G-protein-coupled receptors (GPCRs) and ion channels. Defective de novo cholesterol synthesis, as seen in Smith-Lemli-Opitz syndrome (SLOS), causes typical ciliopathy-like symptoms, suggesting cholesterol deficiency is a core mechanism. We previously identified a pathway where a subset of peroxisomes moves via microtubules to the ciliary base and supplies cholesterol to the ciliary membrane. Furthermore, we found that the mechanosensory cation channel polycystin (PKD1/PKD2) complex, the product of genes underlying Autosomal Dominant Polycystic Kidney Disease (ADPKD), exhibits cholesterol-dependent ciliary localization. Focusing on the ADPKD-associated missense variant p.L517R in the cholesterol-binding site of polycystin-2 (PKD2), we generated mutant mice that displayed ciliopathy spectrums, including situs inversus and polycystic kidneys. The L517R mutant protein showed impaired ciliary localization despite normal channel activity. Intriguingly, exogenous cholesterol administration rescued the ciliary trafficking defect of PKD2 and the expanded epithelial lumen structure in the Zellweger syndrome-modeled cells (peroxisome biogenesis disorder) but not in the PKD2 L517R mutant cells. These findings indicate that the ability of PKD2 to directly bind ciliary membrane cholesterol is essential to prevent ADPKD. This review highlights ciliary cholesterol as a potential therapeutic target for ADPKD.