Desmin-related cardiomyopathy in transgenic mice: A cardiac amyloidosis
Desmin-related cardiomyopathy in transgenic mice: A cardiac amyloidosis
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DOI：
10.1073/pnas.0401900101
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发表时间：
2004-07-06
影响因子：
11.1
通讯作者：
Robbins, J
中科院分区：
文献类型：
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作者：
Sanbe, A;Osinska, H;Robbins, J
小热休克蛋白α - b -结晶蛋白（CryAB(R120G)）的R120G错义突变可引起心肌病（DRM）。DRM的特点是形成含有CryAB和desmin的聚集体，并且可以通过突变蛋白的心脏特异性表达在转基因小鼠中重现。在本文中，我们发现CryAB（R120G）的表达导致DRMs特征的电子致密体的形成，并将这些体鉴定为神经退行性疾病特征的聚集体。转染含有CryAB（R120G）的腺病毒的心肌细胞证实了CryAB（R120G）表达对聚合体形成的必要性和充分性。这些聚集体与淀粉样变性疾病中发现的低聚蛋白聚集体的共性被高水平淀粉样低聚物的存在所证实，淀粉样低聚物可能代表淀粉样疾病的主要毒性物种。这些低聚淀粉样蛋白中间体也存在于许多人类扩张型和肥厚型心肌病的心肌细胞中。
An R120G missense mutation in the small heat shock protein alpha-B-crystallin (CryAB(R120G)) causes desmin-related cardiomyopathy (DRM). DRM is characterized by the formation of aggregates containing CryAB and desmin, and it can be recapitulated in transgenic mice by cardiac-specific expression of the mutant protein. In this article, we show that expression of CryAB(R120G) leads to the formation of electron-dense bodies characteristic of the DRMs and identify these bodies as aggresomes, which are characteristic of the neurodegenerative diseases. Cardiomyocytes transfected with adenovirus containing CryAB(R120G) establish the necessity and sufficiency of CryAB(R120G) expression for aggresome formation. The commonality of these aggresomes with oligomeric protein aggregates found in the amyloid-related degenerative diseases was corroborated by the presence of high levels of amyloid oligomers that may represent a primary toxic species in the amyloid diseases. These oligomeric amyloid intermediates are present also in cardiomyocytes derived from many human dilated and hypertrophic cardiomyopathies.