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

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 pathogenes...

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Autores principales: Guan, Jian, Mishra, Shikha, Qiu, Yiling, Shi, Jianru, Trudeau, Kyle, Las, Guy, Liesa, Marc, Shirihai, Orian S, Connors, Lawreen H, Seldin, David C, Falk, Rodney H, MacRae, Calum A, Liao, Ronglih
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237473/
https://www.ncbi.nlm.nih.gov/pubmed/25319546
http://dx.doi.org/10.15252/emmm.201404190
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author Guan, Jian
Mishra, Shikha
Qiu, Yiling
Shi, Jianru
Trudeau, Kyle
Las, Guy
Liesa, Marc
Shirihai, Orian S
Connors, Lawreen H
Seldin, David C
Falk, Rodney H
MacRae, Calum A
Liao, Ronglih
author_facet Guan, Jian
Mishra, Shikha
Qiu, Yiling
Shi, Jianru
Trudeau, Kyle
Las, Guy
Liesa, Marc
Shirihai, Orian S
Connors, Lawreen H
Seldin, David C
Falk, Rodney H
MacRae, Calum A
Liao, Ronglih
author_sort Guan, Jian
collection PubMed
description 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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spelling pubmed-42374732014-12-04 Lysosomal dysfunction and impaired autophagy underlie the pathogenesis of amyloidogenic light chain-mediated cardiotoxicity Guan, Jian Mishra, Shikha Qiu, Yiling Shi, Jianru Trudeau, Kyle Las, Guy Liesa, Marc Shirihai, Orian S Connors, Lawreen H Seldin, David C Falk, Rodney H MacRae, Calum A Liao, Ronglih EMBO Mol Med Research Articles 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. BlackWell Publishing Ltd 2014-11 2014-10-15 /pmc/articles/PMC4237473/ /pubmed/25319546 http://dx.doi.org/10.15252/emmm.201404190 Text en © 2014 The Authors. Published under the terms of the CC BY 4.0 license http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Guan, Jian
Mishra, Shikha
Qiu, Yiling
Shi, Jianru
Trudeau, Kyle
Las, Guy
Liesa, Marc
Shirihai, Orian S
Connors, Lawreen H
Seldin, David C
Falk, Rodney H
MacRae, Calum A
Liao, Ronglih
Lysosomal dysfunction and impaired autophagy underlie the pathogenesis of amyloidogenic light chain-mediated cardiotoxicity
title Lysosomal dysfunction and impaired autophagy underlie the pathogenesis of amyloidogenic light chain-mediated cardiotoxicity
title_full Lysosomal dysfunction and impaired autophagy underlie the pathogenesis of amyloidogenic light chain-mediated cardiotoxicity
title_fullStr Lysosomal dysfunction and impaired autophagy underlie the pathogenesis of amyloidogenic light chain-mediated cardiotoxicity
title_full_unstemmed Lysosomal dysfunction and impaired autophagy underlie the pathogenesis of amyloidogenic light chain-mediated cardiotoxicity
title_short Lysosomal dysfunction and impaired autophagy underlie the pathogenesis of amyloidogenic light chain-mediated cardiotoxicity
title_sort lysosomal dysfunction and impaired autophagy underlie the pathogenesis of amyloidogenic light chain-mediated cardiotoxicity
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237473/
https://www.ncbi.nlm.nih.gov/pubmed/25319546
http://dx.doi.org/10.15252/emmm.201404190
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