Pathophysiological significance of cholesterol in ciliopathies.

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.