Changes in the expression of the Alzheimer’s disease-associated presenilin gene in drosophila heart leads to cardiac dysfunction.
Changes in the expression of the Alzheimer’s disease-associated presenilin gene in drosophila heart leads to cardiac dysfunction.
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DOI：
10.2174/156720511795563746
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发表时间：
2011-05
影响因子：
2.1
通讯作者：
Tanzi RE
中科院分区：
文献类型：
--
作者：
Li A;Zhou C;Moore J;Zhang P;Tsai TH;Lee HC;Romano DM;McKee ML;Schoenfeld DA;Serra MJ;Raygor K;Cantiello HF;Fujimoto JG;Tanzi RE
早老素基因的突变导致了大多数早发性家族性阿尔茨海默病。最近，早老素突变已在扩张型心肌病（DCM）患者中被发现，DCM是心力衰竭的常见原因，也是心脏移植患者中最常见的诊断。然而，早老素突变导致AD或DCM的分子机制尚不清楚。我们利用转基因果蝇模型和光学相干断层扫描成像技术分析了活的成年果蝇的心脏功能。果蝇早老素（dPsn）同源基因的沉默导致心率显著降低，舒张末期垂直尺寸显著随年龄增加。相反，dPsn的过表达增加了心率。dPsn的过表达或沉默导致心律失常，并伴有心肌原纤维缺陷和线粒体损伤。采用实时RT-PCR定量测定心肌细胞钙通道受体活性。沉默dPsn后，dIP3R表达升高，dSERCA表达降低；dPsn过表达导致dRyR表达降低。此外，dPsn在翅盘的过表达导致了翅表型的丧失和无翅表达的减少。我们的数据提供了新的证据，表明早老素水平的变化导致心功能障碍，这是由于钙通道受体活性异常和Wnt信号转导中断，表明早老素突变在DCM发病中的致病作用。
Mutations in the presenilin genes cause the majority of early-onset familial Alzheimer’s disease. Recently, presenilin mutations have been identified in patients with dilated cardiomyopathy (DCM), a common cause of heart failure and the most prevalent diagnosis in cardiac transplantation patients. However, the molecular mechanisms, by which presenilin mutations lead to either AD or DCM, are not yet understood. We have employed transgenic Drosophila models and optical coherence tomography imaging technology to analyze cardiac function in live adult Drosophila. Silencing of Drosophila ortholog of presenilins (dPsn) led to significantly reduced heart rate and remarkably age-dependent increase in end-diastolic vertical dimensions. In contrast, overexpression of dPsn increased heart rate. Either overexpression or silencing of dPsn resulted in irregular heartbeat rhythms accompanied by cardiomyofibril defects and mitochondrial impairment. The calcium channel receptor activities in cardiac cells were quantitatively determined via real-time RT-PCR. Silencing of dPsn elevated dIP3R expression, and reduced dSERCA expression; overexprerssion of dPsn led to reduced dRyR expression. Moreover, overexpression of dPsn in wing disc resulted in loss of wing phenotype and reduced expression of wingless. Our data provide novel evidence that changes in presenilin level leads to cardiac dysfunction, owing to aberrant calcium channel receptor activities and disrupted Wnt signaling transduction, indicating a pathogenic role for presenilin mutations in DCM pathogenesis.
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DOI：
10.1016/0735-1097(95)00148-s
发表时间：
1995-07-01
影响因子：
24
作者：
GROGAN, M;REDFIELD, MM;RODEHEFFER, RJ
通讯作者：
RODEHEFFER, RJ
影响因子：
3.5
作者：
Murayama, M;Tanaka, S;Takashima, A
通讯作者：
Takashima, A
DOI：
10.1073/pnas.0609278104
发表时间：
2007-03-06
影响因子：
11.1
作者：
Ocorr, Karen;Reeves, Nick L.;Bodmer, Rolf
通讯作者：
Bodmer, Rolf
影响因子：
9.8
作者：
Li, Duanxiang;Parks, Sharie B.;Hershberger, Ray E.
通讯作者：
Hershberger, Ray E.
影响因子：
5.3
作者：
Ocorr, Karen;Akasaka, Takeshi;Bodmer, Rolf
通讯作者：
Bodmer, Rolf