Clusterin regulates transthyretin amyloidosis.
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.
Lee
Ko-Woon
KW
Department of Anatomy and Neurobiology, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Gyeongnam 660-751, South Korea.
Lee
Dong-Hoon
DH
Son
Hosun
H
Kim
Yoon-Sook
YS
Park
Jae-Yong
JY
Roh
Gu-Seob
GS
Kim
Hyun-Joon
HJ
Kang
Sang-Soo
SS
Cho
Gyeong-Jae
GJ
Choi
Wan-Sung
WS
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
D000682:Amyloid; D051152:Clusterin; D011228:Prealbumin