title: Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA 02125, USA.
authors.forename: Davide
authors.initials: D
authors.lastname: Gianni
authors.forename: Airong
authors.initials: A
authors.lastname: Li
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Tesco
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: McKay
authors.forename: John
authors.initials: J
authors.lastname: Moore
authors.forename: Kunal
authors.initials: K
authors.lastname: Raygor
authors.forename: Marcello
authors.initials: M
authors.lastname: Rota
authors.forename: Judith K
authors.initials: JK
authors.lastname: Gwathmey
authors.forename: G William
authors.initials: GW
authors.lastname: Dec
authors.forename: Thomas
authors.initials: T
authors.lastname: Aretz
authors.forename: Annarosa
authors.initials: A
authors.lastname: Leri
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Semigran
authors.forename: Piero
authors.initials: P
authors.lastname: Anversa
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Macgillivray
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.forename: Federica
authors.initials: F
authors.lastname: del Monte
mesh_terms: D000328:Adult; D000368:Aged; D000682:Amyloid / Q000032:analysis; D016229:Amyloid beta-Peptides / Q000032:analysis; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D053764:Presenilin-1 / Q000235:genetics*; D053766:Presenilin-2 / Q000235:genetics; D011506:Proteins / Q000737:chemistry*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D011506:Proteins; D002118:Calcium