Evidence for a Functional Role of the Molecular Chaperone Clusterin in Amyloidotic Cardiomyopathy

Abstract

Molecular chaperones, including the extracellular protein clusterin (CLU), play a significant role in maintaining proteostasis; they have a unique capacity to bind and stabilize non-native protein conformations, prevent aggregation, and keep proteins in a soluble foldingcompetent state. In this study, we investigated amyloidinfiltrated cardiac tissue for the presence of CLU and measured serum levels of CLU in patients with and without amyloidotic cardiomyopathy (CMP). Cardiac tissues containing amyloid deposits composed of either transthyretin (TTR) or Ig light chain from nine patients with amyloidotic CMP were examined for the presence of CLU using immunohistochemical techniques. CLU staining coincided with the extracellular myocardial amyloid deposits in tissues from patients with familial TTR, senile systemic, and Ig light chain amyloidosis. The association of CLU with cardiac amyloid deposits was confirmed by immunogold electron microscopy. Serum concentrations of CLU were measured in familial TTR, senile systemic, and Ig light chain amyloidosis patient groups and compared with both age-matched healthy controls and with patients with CMP unrelated to amyloid disease. Subset analysis of disease cohorts, based on cardiac involvement, indicated that decreased serum CLU concentrations were associated with amyloidotic CMP. Taken together, these results suggest that CLU may play a pathogenetic role in TTR and Ig light chain amyloidoses and amyloidotic CMP.

Protective role of clusterin in preserving endothelial function in AL amyloidosis

“…Because of these effects, it has been proposed that the strong association between clusterin levels and AD severity reflects a neuroprotective response, rather than what was previously thought to be etiopathologic effect 2 , although this issue remains controversial. Recently, clusterin was found in cardiac amyloid deposits, with serum clusterin reduced in AL patients 1 . This led to suggestions that a pathogenic role exists for clusterin in AL 1 .…”

“…Yet the beneficial versus pathologic role of clusterin, a chaperone glycoprotein, in Alzheimer’s disease (AD) or light chain amyloidosis (AL) remains controversial 1–3 . AL involves overproduction of amyloidogenic immunoglobulin light chain proteins (LC) that cause toxicity to blood vessels 4 , cardiac and other tissues with high mortality and morbidity rates to this day.…”

Reliable typing of systemic amyloidoses through proteomic analysis of subcutaneous adipose tissue

“…These 4 proteins (LC , LC , TTR, and serum amyloid A [SAA]), identified by proteomic analysis, matched those expected to constitute the fibrils according to IEM (Figure 1; supplemental Table 3). In addition, other proteins (supplemental Table 3) were found to be over-represented across the various amyloidoses, including clusterin, 17 apolipoprotein E, 18,19 apolipoprotein A-IV, 20 vitronectin, 18 basement membrane-specific heparan sulfate proteoglycan core protein, 21 sushi-repeat-containing protein, and serum amyloid P. 22 Most of these had previously been described as associated with amyloid fibrils and involved in the mechanisms of amyloid formation; this confirms that MudPIT can fully characterize the deposits in whole adipose tissue and constitutes an internal validation parameter. In addition, sushi-repeat-containing protein may play a role in amyloid disease; indeed, it is secreted by adipocytes 23 and may intervene in adipogenic differentiation, 24 regulation of body weight, and metabolism.…”

The repertoire of λ light chains causing predominant amyloid heart involvement and identification of a preferentially involved germline gene, IGLV1-44

“…It is conceivable that IGVL1-44 gene segment owns germline-encoded structural features that could account for the preferential targeting to the heart. Interaction with extracellular chaperones, as recently outlined for clusterin, 30 might be a possibility.…”