Lysosomal dysfunction and impaired autophagy underlie the pathogenesis of amyloidogenic light chain-mediated cardiotoxicity.
Lysosomal dysfunction and impaired autophagy underlie the pathogenesis of amyloidogenic light chain-mediated cardiotoxicity.
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DOI：
10.15252/emmm.201404190
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发表时间：
2014-11
影响因子：
11.1
通讯作者：
Liao R
中科院分区：
文献类型：
--
作者：
Guan J;Mishra S;Qiu Y;Shi J;Trudeau K;Las G;Liesa M;Shirihai OS;Connors LH;Seldin DC;Falk RH;MacRae CA;Liao R
AL淀粉样变性是淀粉样原性免疫球蛋白轻链（LC）蛋白克隆产生的结果，通常导致迅速进展和致命的淀粉样心肌病。最近的研究发现淀粉样蛋白源性LC直接引发心肌病发病机制的心脏毒性反应；然而，导致这种蛋白质毒性的机制尚不清楚。利用从淀粉样心肌病患者分离的人类淀粉样蛋白LC，我们发现自噬通量的失调是介导淀粉样蛋白LC蛋白毒性的关键。在体内淀粉样蛋白心脏毒性斑马鱼模型中，使用雷帕霉素进行药物干预恢复自噬通量可防止淀粉样蛋白轻链蛋白诱导的病理，包括细胞和器官水平的收缩功能障碍和细胞死亡，并延长存活时间。在机制上，我们发现溶酶体功能受损是自噬缺陷和淀粉样变性lc诱导的蛋白质毒性的主要原因。总的来说，这些发现详细说明了AL淀粉样蛋白心肌病的下游分子机制，并强调了淀粉样蛋白心肌病患者自噬和溶酶体功能障碍的潜在靶向。
AL amyloidosis is the consequence of clonal production of amyloidogenic immunoglobulin light chain (LC) proteins, often resulting in a rapidly progressive and fatal amyloid cardiomyopathy. Recent work has found that amyloidogenic LC directly initiate a cardio-toxic response underlying the pathogenesis of the cardiomyopathy; however, the mechanisms that contribute to this proteotoxicity remain unknown. Using human amyloidogenic LC isolated from patients with amyloid cardiomyopathy, we reveal that dysregulation of autophagic flux is critical for mediating amyloidogenic LC proteotoxicity. Restoration of autophagic flux by pharmacological intervention using rapamycin protected against amyloidogenic light chain protein-induced pathologies including contractile dysfunction and cell death at the cellular and organ level and also prolonged survival in an in vivo zebrafish model of amyloid cardiotoxicity. Mechanistically, we identify impaired lysosomal function to be the major cause of defective autophagy and amyloidogenic LC-induced proteotoxicity. Collectively, these findings detail the downstream molecular mechanisms underlying AL amyloid cardiomyopathy and highlight potential targeting of autophagy and lysosomal dysfunction in patients with amyloid cardiomyopathy.
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影响因子：
11.1
作者：
Pastore, Nunzia;Blomenkamp, Keith;Annunziata, Fabio;Piccolo, Pasquale;Mithbaokar, Pratibha;Sepe, Rosa Maria;Vetrini, Francesco;Palmer, Donna;Ng, Philip;Polishchuk, Elena;Iacobacci, Simona;Polishchuk, Roman;Teckman, Jeffrey;Ballabio, Andrea;Brunetti-Pierri, Nicola
通讯作者：
Brunetti-Pierri, Nicola
影响因子：
5.5
作者：
Shin, Jordan T.;Ward, Jennifer E.;Seldin, David C.
通讯作者：
Seldin, David C.
影响因子：
37.8
作者：
Liao, RL;Jain, M;Apstein, CS
通讯作者：
Apstein, CS
DOI：
10.1152/ajpheart.00186.2013
发表时间：
2013-07-01
影响因子：
4.8
作者：
Mishra, Shikha;Guan, Jian;Liao, Ronglih
通讯作者：
Liao, Ronglih
DOI：
10.1152/ajpheart.00503.2011
发表时间：
2011-12-01
影响因子：
4.8
作者：
Migrino, Raymond Q.;Truran, Seth;Hari, Parameswaran
通讯作者：
Hari, Parameswaran