Pathophysiological significance of cholesterol in ciliopathies

Primary cilia are sensory organelles essential for cellular signaling, the dysfunction of which causes ciliopathies, characterized by polycystic kidney disease, retinopathy, and developmental anomalies. Here, we review recent studies which have shown that cholesterol is a critical mediator of ciliary function and the pathogenesis of ciliopathies. Ciliary membranes show distinct cholesterol enrichment that is essential for the physiological function of various G-protein-coupled receptors and ion channels. Defects in de novo cholesterol synthesis (Smith-Lemli-Opitz syndrome) and peroxisome-facilitated cholesterol trafficking to ciliary membranes (Zellweger syndrome) result in ciliopathy-like phenotypes, establishing ciliary cholesterol insufficiency as a novel pathological mechanism. The polycystin complex associated autosomal dominant polycystic kidney disease localizes into ciliary membranes in a cholesterol-dependent manner. Specific cholesterol-binding sites in polycystin-2 are crucial for the distribution of cholesterol to cilia, while pathogenic mutations at these sites disrupt these interactions. We also discuss the previously underappreciated connections between ciliopathies, cholesterol, and other disorders such as cancer and neurodegenerative diseases, and opportunities for manipulating cholesterol for novel therapeutic strategies.