Protein Aggregates and Novel Presenilin Gene Variants in Idiopathic Dilated Cardiomyopathy

• 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: Adult; Aged; Amyloid - analysis; Amyloid beta-Peptides - analysis; Associated diseases and complications; Biological and medical sciences; Blood and lymphatic vessels; Calcium - metabolism; Cardiology. Vascular system; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - metabolism; Diabetes. Impaired glucose tolerance; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Female; Humans; Immunohistochemistry; Male; Medical sciences; Middle Aged; Mutation; Polymorphism, Single Nucleotide; Presenilin-1 - genetics; Presenilin-2 - genetics; Proteins - chemistry
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.109.879510

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.