title: Clusterin regulates transthyretin amyloidosis.
abstract: Transthyretin (TTR) is a human disease-associated amyloidogenic protein that has been implicated in senile systemic amyloidosis (SSA) and familial amyloidotic polyneuropathy (FAP). FAP typically results in severe and early-onset disease, and the only therapy established so far is liver transplantation; thus, developing new strategies for treating FAP is of paramount interest. Clusterin has recently been proposed to play a role as an extracellular molecular chaperone, affecting the fibril formation of amyloidogenic proteins. The ability of clusterin to influence amyloid fibril formation prompted us to investigate whether clusterin is capable of inhibiting TTR amyloidosis. Here, we report that clusterin strongly interacts with wild-type TTR and TTR variants V30M and L55P under acidic conditions, and blocks the amyloid fibril formation of TTR variants. In particular, the amyloid fibril formation of V30M TTR in the presence of clusterin is reduced to level similar to wild-type TTR. We also demonstrated that clusterin is an effective inhibitor of L55P TTR amyloidosis, the most aggressive form of TTR diseases. The mechanism by which clusterin inhibits TTR amyloidosis appears to be through stabilization of TTR tetrameric structure. These findings suggest the possibility of using clusterin as a therapeutic agent for TTR amyloidosis.
authors: Department of Anatomy and Neurobiology, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Gyeongnam 660-751, South Korea.
authors: Ko-Woon
authors: KW
authors: Lee
authors: Dong-Hoon
authors: DH
authors: Lee
authors: Hosun
authors: H
authors: Son
authors: Yoon-Sook
authors: YS
authors: Kim
authors: Jae-Yong
authors: JY
authors: Park
authors: Gu-Seob
authors: GS
authors: Roh
authors: Hyun-Joon
authors: HJ
authors: Kim
authors: Sang-Soo
authors: SS
authors: Kang
authors: Gyeong-Jae
authors: GJ
authors: Cho
authors: Wan-Sung
authors: WS
authors: Choi
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D028227:Amyloid Neuropathies, Familial / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D051152:Clusterin / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism*; D051381:Rats
chemical_list: D000682:Amyloid; D051152:Clusterin; D011228:Prealbumin