Loading…

Protein Aggregates and Novel Presenilin Gene Variants in Idiopathic Dilated Cardiomyopathy

Heart failure is a debilitating condition resulting in severe disability and death. In a subset of cases, clustered as idiopathic dilated cardiomyopathy (iDCM), the origin of heart failure is unknown. In the brain of patients with dementia, proteinaceous aggregates and abnormal oligomeric assemblies...

Full description

Saved in:
Bibliographic Details
Published in:Circulation (New York, N.Y.) N.Y.), 2010-03, Vol.121 (10), p.1216-1226
Main Authors: GIANNI, Davide, AIRONG LI, LERI, Annarosa, SEMIGRAN, Marc J, ANVERSA, Piero, MACGILLIVRAY, Thomas E, TANZI, Rudolph E, DEL MONTE, Federica, TESCO, Giuseppina, MCKAY, Kenneth M, MOORE, John, RAYGOR, Kunal, ROTA, Marcello, GWATHMEY, Judith K, DEC, G. William, ARETZ, Thomas
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Heart failure is a debilitating condition resulting in severe disability and death. In a subset of cases, clustered as idiopathic dilated cardiomyopathy (iDCM), the origin of heart failure is unknown. In the brain of patients with dementia, proteinaceous aggregates and abnormal oligomeric assemblies of beta-amyloid impair cell function and lead to cell death. We have similarly characterized fibrillar and oligomeric assemblies in the hearts of iDCM patients, pointing to abnormal protein aggregation as a determinant of iDCM. We also showed that oligomers alter myocyte Ca(2+) homeostasis. Additionally, we have identified 2 new sequence variants in the presenilin-1 (PSEN1) gene promoter leading to reduced gene and protein expression. We also show that presenilin-1 coimmunoprecipitates with SERCA2a. On the basis of these findings, we propose that 2 mechanisms may link protein aggregation and cardiac function: oligomer-induced changes on Ca(2+) handling and a direct effect of PSEN1 sequence variants on excitation-contraction coupling protein function.
ISSN:0009-7322
1524-4539
DOI:10.1161/CIRCULATIONAHA.109.879510