- \n
- Cholesterol anchors polycystin (ion channel) proteins to the primary cilia, thus preventing the development of polycystic kidney disease.<\/li>\n
- The polycystin protein is responsible for transporting and accumulating cholesterol into primary cilia, as well as for functioning as an ion channel in primary cilia.<\/li>\n
- These findings open up new therapeutic possibilities for both rare ciliopathies and more common diseases including cancer and psychiatric and neurological disorders.<\/li>\n<\/ul>\n
\u00a0A collaborative research team from Yamaguchi University, Hiroshima University, and Shimane University in Japan has found that cholesterol confines polycystin proteins, which sense the extracellular fluid flow, to the cell membrane of primary cilia, allowing the high sensitivity of primary cilia as a cellular antenna.
\u00a0Excess cholesterol is widely known to contribute to an increased risk of hyperlipidemia and atherosclerosis. However, the mechanisms through which cholesterol deficiency leads to ciliopathy symptoms, such as multiple cystic kidneys, were not well understood. In the present study, analysis of cultured cells and mice with the ADPKD-mutated polycystin gene, using genome editing technology, showed ciliopathy characterized by multiple cystic kidneys and situs inversus by failing to localize polycystins on primary cilia due to the loss of the confinement effect of cholesterol. This research indicates that supplying cholesterol to primary cilia will be beneficial as a new treatment and is expected to lead to the development of new drugs for ciliopathies. Given that many proteins associated with \u201ccancer\u201d and \u201cpsychiatric\/neurological diseases\u201d are concentrated in primary cilia, this research is anticipated to aid in the development of new treatments for both rare genetic ciliopathies and more prevalent diseases.<\/p>\nBackground<\/h4>\n
\u00a0Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in the PKD genes, is the most common inherited chronic renal disease with no curative therapy and an estimated incidence of 1 in 4,000 to 8,000 patients in Japan. The PKD1 (polycystin-1 gene) and PKD2 (polycystin-2 gene) are the genes responsible for ADPKD. The polycystin-1\/ polycystin-2 protein complex is located in the primary cilia of epithelial cells that form tubules and collecting ducts, regulating the thickness of these structures by inducing Ca2+<\/sup> influx into the cells in response to urine flow.
\u00a0Primary cilia are single hair-like structures that develop on the cell surface and are found throughout the body, in addition to the kidney. The ciliary membrane, which covers primary cilia, is known to be rich in cholesterol. In recent years, advanced electron microscopy has suggested that the polycystin-2 protein binds to cholesterol. However, the mechanism by which lowering cholesterol causes polycystic kidney disease is not well understood.<\/p>\nOverview of research achievement<\/h4>\n
\u00a0Zellweger syndrome, a hereditary disease characterized by defective peroxisomes\u2014cell organelles responsible for transporting cholesterol to the primary cilia\u2014has been shown to cause polycystic kidney disease. The research team examined the primary cilia of Zellweger syndrome model cells generated with genome editing. They discovered that the polycystin-2 protein and cholesterol did not accumulate in the ciliary membrane (Reference data, Fig. 1). Interestingly, the research team found that cholesterol supplementation to these cells’ primary cilia restored polycystin-2 protein levels to normal and made them functional again. Next, they generated and analyzed cultured cells that have the polycystin-2 gene mutation, which lost its ability to bind cholesterol, as observed in some cases of autosomal dominant polycystic kidney disease (ADPKD) patients. The results showed that polycystin-2 in these mutant cells functions normally as an ion channel but causes a decrease in cholesterol in the ciliary membrane, leading to insufficient accumulation in the primary cilia (Reference data, Fig 1). When mice carrying this mutation were generated by genome editing technology, they were found to be lethally affected at the developmental stage, exhibiting similar symptoms observed in patients with fibrocystic kidney disease, such as multiple cystic kidneys and visceral inversion (Reference data, Figure 2).
\u00a0These results demonstrate for the first time that cholesterol plays a crucial role in confining polycystin-2, an important ion channel, to the ciliary membrane in adequate and sustained amounts. Therefore, the insufficient accumulation and dysfunction of polycystin protein due to low cholesterol levels are implicated in the development of polycystic kidney disease, visceral retroversion, and other ciliopathies (Reference data Fig. 3).<\/p>\nFuture development<\/h4>\n
\u00a0This study has revealed that supplying cholesterol to primary cilia is beneficial as a new treatment for ciliopathies. The Yamaguchi University team is currently developing a drug designed to enhance the accumulation of cholesterol in primary cilia (PCT patent application as of December 2024), which is anticipated to lead to advancements in drug discovery for the treatment of ciliopathies. Furthermore, because numerous molecules associated with cancer and psychiatric and neurological diseases\u2014such as those controlling cell proliferation and hormone receptors influencing human behavior\u2014are concentrated in primary cilia, these research findings are expected to facilitate the development of new treatment methods not only for rare ciliopathies but also for more prevalent diseases.<\/p>\n
Reference data<\/h4>\n
![\"\"](\"https:\/\/ds27i1.cc.yamaguchi-u.ac.jp\/~www-yu\/english\/wp-content\/uploads\/sites\/4\/2025\/02\/25020501_en.png\")
Figure 1.\u3000 Cholesterol and polycystin-2 protein in primary cilia<\/strong>
Cholesterol and polycystin-2 protein were abundant in the primary cilia of wild-type cells (stained green; yellow indicates the basal body (centrosome) located at the base of the primary cilia), they were dramatically reduced in Zellweger syndrome model cells. Cholesterol supplementation to these cells restored the accumulation of polycystin-2 protein in the primary cilia to wild-type cellular levels. In polycystin-2 without cholesterol-binding ability, the accumulation of cholesterol and polycystin-2 protein was also impaired in the primary cilia of ADPKD mutant cells. On the other hand, in mutant cells that retain cholesterol binding, cholesterol supplementation restores polycystin-2 protein accumulation in primary cilia to wild-type cellular levels.<\/p>\n![\"\"](\"https:\/\/ds27i1.cc.yamaguchi-u.ac.jp\/~www-yu\/english\/wp-content\/uploads\/sites\/4\/2025\/02\/25020502_en.jpg\")
Figure 2.\u3000 Cystic kidney in ADPKD mutant mice<\/strong>
ADPKD model mice carrying a genetic mutation that loses the polycystin-2’s cholesterol-binding properties were lethally affected during development and exhibited ciliopathy symptoms such as multiple cystic kidneys that numerous pouch-like structures (cysts) formed in the kidneys and visceral inversion.<\/p>\n![\"\"](\"https:\/\/ds27i1.cc.yamaguchi-u.ac.jp\/~www-yu\/english\/wp-content\/uploads\/sites\/4\/2025\/02\/25020503_en.png\")
<\/p>\nFigure 3.\u3000 Cholesterol prevents multiple cystic kidneys<\/strong>
In normal cells, cholesterol synthesized in the endoplasmic reticulum is transported by peroxisomes to the primary cilia. Cholesterol captures the polycystin-2 protein (an ion channel) in the primary cilia, enabling the primary cilia to function as an antenna for the cell. However, mutations in the polycystin-2 gene lessen cholesterol levels in the primary cilia, resulting in abnormal cell proliferation and osmotic pressure, which leads to polycystic kidney disease.<\/p>\nReference<\/h4>\n
- \n
- Title of original paper<\/strong>: Cholesterol ensures ciliary polycystin-2 localization to prevent polycystic kidney disease<\/li>\n
- Authors<\/strong>: Takeshi Itabashi1,2,10<\/sup>, Kosuke Hosoba3,4,10<\/sup>, Tomoka Morita1,2,10<\/sup>, Sotai Kimura5,6<\/sup>, Kenji Yamaoka7<\/sup>, Moe Hirosawa1,2<\/sup>, Daigo Kobayashi1<\/sup>, Hiroko Kishi1,8<\/sup>, Kodai Kume9<\/sup>, Hiroshi Itoh5<\/sup>, Hideshi Kawakami9<\/sup>, Kouichi Hashimoto7<\/sup>, Takashi Yamamoto3,4<\/sup> and Tatsuo Miyamoto1,2*<\/sup><\/li>\n
- Journal<\/strong>: Life Science Alliance<\/em><\/li>\n
- DOI<\/strong>: https:\/\/doi.org\/10.26508\/lsa.202403063<\/a><\/li>\n
- Affiliations<\/strong>:
1<\/sup> Department of Molecular and Cellular Physiology, Graduate School of Medicine, Yamaguchi University
2<\/sup> Division of Advanced Genome Editing Therapy, Research Institute for Cell Design Medical Science, Yamaguchi University
3<\/sup> Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University
4<\/sup> Program of Mathematical and Life Science, Graduate School of Integrated Sciences for Life, Hiroshima University
5<\/sup> Department of Molecular Pathology, Graduate School of Medicine, Yamaguchi University
6<\/sup> Department of Anatomic Pathology, Hirosaki University Hospital
7<\/sup> Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima University
8<\/sup> Department of Environmental Physiology, Faculty of Medicine, Shimane University
9<\/sup> Department of Molecular Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University
10<\/sup> These authors contributed equally to this work.<\/li>\n<\/ul>\n*Corresponding author\u2019s email: t-miyamoto@ (@ below\u2192yamaguchi-u.ac.jp)<\/div>\n","protected":false},"featured_media":2773,"template":"","meta":[],"_links":{"self":[{"href":"https:\/\/ds27i1.cc.yamaguchi-u.ac.jp\/~www-yu\/english\/wp-json\/wp\/v2\/news\/2770"}],"collection":[{"href":"https:\/\/ds27i1.cc.yamaguchi-u.ac.jp\/~www-yu\/english\/wp-json\/wp\/v2\/news"}],"about":[{"href":"https:\/\/ds27i1.cc.yamaguchi-u.ac.jp\/~www-yu\/english\/wp-json\/wp\/v2\/types\/news"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/ds27i1.cc.yamaguchi-u.ac.jp\/~www-yu\/english\/wp-json\/wp\/v2\/media\/2773"}],"wp:attachment":[{"href":"https:\/\/ds27i1.cc.yamaguchi-u.ac.jp\/~www-yu\/english\/wp-json\/wp\/v2\/media?parent=2770"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}} - Authors<\/strong>: Takeshi Itabashi1,2,10<\/sup>, Kosuke Hosoba3,4,10<\/sup>, Tomoka Morita1,2,10<\/sup>, Sotai Kimura5,6<\/sup>, Kenji Yamaoka7<\/sup>, Moe Hirosawa1,2<\/sup>, Daigo Kobayashi1<\/sup>, Hiroko Kishi1,8<\/sup>, Kodai Kume9<\/sup>, Hiroshi Itoh5<\/sup>, Hideshi Kawakami9<\/sup>, Kouichi Hashimoto7<\/sup>, Takashi Yamamoto3,4<\/sup> and Tatsuo Miyamoto1,2*<\/sup><\/li>\n
- Title of original paper<\/strong>: Cholesterol ensures ciliary polycystin-2 localization to prevent polycystic kidney disease<\/li>\n