Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA 02125, USA.
Circulation. 2010 Mar 16;121(10):1216-26. doi: 10.1161/CIRCULATIONAHA.109.879510. Epub 2010 Mar 1.
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.
心力衰竭是一种导致严重残疾和死亡的衰弱性疾病。在一些情况下，如特发性扩张型心肌病（iDCM），心力衰竭的起源是未知的。在痴呆症患者的大脑中，β淀粉样蛋白的蛋白聚集物和异常低聚物组装会损害细胞功能并导致细胞死亡。
我们同样描述了 iDCM 患者心脏中的纤维状和低聚物组装，指出异常蛋白聚集是 iDCM 的决定因素。我们还表明，低聚物改变了心肌细胞的 Ca(2+)稳态。此外，我们在早老素-1（PSEN1）基因启动子中发现了 2 个新的序列变异，导致基因和蛋白表达减少。我们还表明早老素-1与 SERCA2a 共免疫沉淀。
基于这些发现，我们提出了 2 种可能将蛋白聚集和心脏功能联系起来的机制：低聚物诱导的 Ca(2+)处理变化和 PSEN1 序列变异对兴奋-收缩偶联蛋白功能的直接影响。
