Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy.
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.
Gianni
Davide
D
Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA 02125, USA.
Li
Airong
A
Tesco
Giuseppina
G
McKay
Kenneth M
KM
Moore
John
J
Raygor
Kunal
K
Rota
Marcello
M
Gwathmey
Judith K
JK
Dec
G William
GW
Aretz
Thomas
T
Leri
Annarosa
A
Semigran
Marc J
MJ
Anversa
Piero
P
Macgillivray
Thomas E
TE
Tanzi
Rudolph E
RE
del Monte
Federica
F
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*
D000682:Amyloid; D016229:Amyloid beta-Peptides; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D011506:Proteins; D002118:Calcium