Mouse senile amyloid fibrils deposited in skeletal muscle exhibit amyloidosis-enhancing activity.
Mouse senile amyloid fibrils deposited in skeletal muscle exhibit amyloidosis-enhancing activity.
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DOI：
10.1371/journal.ppat.1000914
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发表时间：
2010-05-20
期刊：
影响因子：
6.7
通讯作者：
Higuchi K
中科院分区：
文献类型：
--
作者：
Qian J;Yan J;Ge F;Zhang B;Fu X;Tomozawa H;Sawashita J;Mori M;Higuchi K
淀粉样变性描述了一组蛋白质折叠疾病，其中淀粉样蛋白作为细纤维异常沉积在器官和/或组织中。小鼠老年淀粉样变性是一种载脂蛋白 A-II (apoA-II) 以淀粉样原纤维 (AApoAII) 形式沉积的疾病，并且可以通过患有淀粉样变性的小鼠排出的粪便和乳汁从一种动物传播到另一种动物。因此，小鼠AApoAII淀粉样变性已被证明是一种“传染性疾病”。在本研究中，为了进一步表征淀粉样变性的传播性，将AApoAII淀粉样蛋白原纤维注射到转基因Apoa2cTg+/-和正常R1.P1-Apoa2c小鼠中以诱导AApoAII系统性淀粉样变性。两个月后，在受淀粉样蛋白影响的小鼠的骨骼肌中发现了 AApoAII 淀粉样蛋白沉积物，主要是在血管和肌纤维周围的间质组织中。当从骨骼肌提取的淀粉样原纤维进行蛋白质印迹分析时，检测到apoA-II。从肌肉中分离出的淀粉样蛋白原纤维部分不仅证明了淀粉样蛋白原纤维的结构，而且还可以根据其原纤维构象在年轻小鼠中诱导淀粉样变性。这些发现提出了淀粉样变性的可能发病机制：淀粉样蛋白原纤维构象通过肌肉的传递，并为淀粉样蛋白疾病的病因学提供了新的线索。 “淀粉样变性”是一组以组织中细纤维沉积为特征的蛋白质折叠疾病，是一种常见的蛋白质代谢紊乱，可以是获得性、遗传性和/或年龄相关的。最近，在各种淀粉样变性中发现了类似朊病毒的传播。小鼠老年淀粉样变性中的 AApoAII 淀粉样原纤维表现出可传播性。例如，摄入的AApoAII淀粉样蛋白纤维（从小鼠体内排出并包含在粪便或乳汁中）充当将apoA-II淀粉样蛋白前体蛋白转变为纤维形式的种子，并导致小鼠老年淀粉样变性。然而，通过其他途径的传播尚未确定。在这里，我们在转基因Apoa2cTg+/-和正常R1.P1-Apoa2c小鼠中诱导AApoAII系统性淀粉样变性，以分析小鼠老年淀粉样变性通过肌肉组织的传播性。在这项研究中，我们不仅检测到了沉积在各种骨骼肌中的AApoAII，而且发现它可以诱导AApoAII淀粉样变性的继发性传播。这是非朊病毒系统性淀粉样变性中通过骨骼肌传播的第一个证据。这种传播途径为系统性淀粉样变性的食源性发病机制和病因学的可能性提供了新的见解。
Amyloidosis describes a group of protein folding diseases in which amyloid proteins are abnormally deposited in organs and/or tissues as fine fibrils. Mouse senile amyloidosis is a disorder in which apolipoprotein A-II (apoA-II) deposits as amyloid fibrils (AApoAII) and can be transmitted from one animal to another both by the feces and milk excreted by mice with amyloidosis. Thus, mouse AApoAII amyloidosis has been demonstrated to be a “transmissible disease”. In this study, to further characterize the transmissibility of amyloidosis, AApoAII amyloid fibrils were injected into transgenic Apoa2cTg+/− and normal R1.P1-Apoa2c mice to induce AApoAII systemic amyloidosis. Two months later, AApoAII amyloid deposits were found in the skeletal muscles of amyloid-affected mice, primarily in the blood vessels and in the interstitial tissues surrounding muscle fibers. When amyloid fibrils extracted from the skeletal muscles were subjected to Western blot analysis, apoA-II was detected. Amyloid fibril fractions isolated from the muscles not only demonstrated the structure of amyloid fibrils but could also induce amyloidosis in young mice depending on its fibril conformation. These findings present a possible pathogenesis of amyloidosis: transmission of amyloid fibril conformation through muscle, and shed new light on the etiology involved in amyloid disorders. “Amyloidosis”, a group of protein folding diseases characterized by deposition of fine fibrils in tissues, is a common disorder of protein metabolism and can be acquired, inherited and/or age-associated. Recently, prion-like transmission has been found in various amyloidoses. AApoAII amyloid fibrils in mouse senile amyloidosis have exhibited transmissibility. For instance, ingested AApoAII amyloid fibrils, which were excreted from mice and contained in feces or milk, function as seeds for changing apoA-II amyloid precursor protein to the fibrillar form and cause mouse senile amyloidosis. However, transmissibility through other pathways has not yet been established. Here, we induced AApoAII systemic amyloidosis in transgenic Apoa2cTg+/− and normal R1.P1-Apoa2c mice to analyze the transmissibility of mouse senile amyloidosis through muscle tissues. In this study, we not only detected AApoAII deposited in various skeletal muscles, but also found that it could induce secondary transmission of AApoAII amyloidosis. This is the first evidence of transmission through skeletal muscles in non-prion systemic amyloidosis. This pathway of transmission provides new insight into the potential for food-borne pathogenesis and etiology of systemic amyloidosis.
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影响因子：
82.9
作者：
Andréoletti, O;Simon, S;Schelcher, F
通讯作者：
Schelcher, F
DOI：
10.1073/pnas.092205999
发表时间：
2002-05-14
影响因子：
11.1
作者：
Lundmark, K;Westermark, GT;Westermark, P
通讯作者：
Westermark, P
影响因子：
2.4
作者：
Hamir, AN;Miller, JM;Cutlip, RC
通讯作者：
Cutlip, RC
影响因子：
7.3
作者：
Kovács, GG;Kalev, O;Budka, H
通讯作者：
Budka, H
影响因子：
4.1
作者：
HIGUCHI, K;KITAGAWA, K;TAKEDA, T
通讯作者：
TAKEDA, T