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.
Highlights
AL or light chain amyloidosis is the most commonly diagnosed systemic amyloidosis in the United States and Europe (Merlini et al, 2011), in which widespread tissue infiltration and deposition of amyloid fibrils derived from clonal immunoglobulin light chain (LC) proteins causes multi-organ dysfunction
Using the reactive oxygen species (ROS)-sensitive fluorescent dye, DCFDA, we found that increased amyloidogenic light chain proteins (AL-LC)-elicited ROS was abolished with MitoTEMPO to levels comparable to cells treated with vehicle (Veh) or control light chain (Con-LC) proteins isolated from patients with multiple myeloma (Fig 1A)
We further demonstrate that restoration of autophagic flux pharmacologically with rapamycin or genetically through overexpression of TFEB protects against AL-LC cardiotoxicity and may represent a novel therapeutic approach for treatment of amyloid cardiomyopathy
Summary
AL or light chain amyloidosis (formerly known as primary amyloidosis) is the most commonly diagnosed systemic amyloidosis in the United States and Europe (Merlini et al, 2011), in which widespread tissue infiltration and deposition of amyloid fibrils derived from clonal immunoglobulin light chain (LC) proteins causes multi-organ dysfunction. We and others have found that circulating amyloidogenic light chain proteins (AL-LC) directly initiate a potent cardiotoxic effect, independent of fibril deposition, and this cardiotoxicity is critical to manifestations of amyloid cardiomyopathy, both in vitro and in vivo (Liao et al, 2001; Brenner et al, 2004; Migrino et al, 2010, 2011; Shi et al, 2010; Sikkink & Ramirez-Alvarado, 2010; Shin et al, 2012) While these findings have changed our understanding of AL amyloid cardiomyopathy, from one of just passive fibril infiltration to acknowledging a direct proteotoxicity, the basic mechanisms by which this proteotoxicity results in cardiomyopathy remain unknown.
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