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Wiley Open Access, EMBO Molecular Medicine, 11(6), p. 1493-1507, 2014

DOI: 10.15252/emmm.201404190

Wiley Open Access, EMBO Molecular Medicine, 5(7), p. 688-688, 2015

DOI: 10.15252/emmm.201505318

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Lysosomal dysfunction and impaired autophagy underlie the pathogenesis of amyloidogenic light chain-mediated cardiotoxicity

Journal article published in 2014 by Jian Guan, Shikha Mishra, Yiling Qiu, Jianru Shi, Kyle Trudeau, Guy Las, Marc Liesa ORCID, Orian S. Shirihai, David C. Seldin, Lawreen H. Connors ORCID, Rodney H. Falk, Calum A. MacRae, Ronglih Liao
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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.