Pathogenesis of autosomal dominant hereditary spastic paraplegia (SPG6) revealed by a rat model.
Pathogenesis of autosomal dominant hereditary spastic paraplegia (SPG6) revealed by a rat model.
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DOI：
10.1097/nen.0000000000000000
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发表时间：
2013-11
影响因子：
3.2
通讯作者：
Kisanuki YY
中科院分区：
文献类型：
--
作者：
Watanabe F;Arnold WD;Hammer RE;Ghodsizadeh O;Moti H;Schumer M;Hashmi A;Hernandez A;Sneh A;Sahenk Z;Kisanuki YY
补充数字内容可在文本中找到。遗传性痉挛性截瘫（HSP）的特征是下肢进行性痉挛和无力，这是由长度依赖性中枢至外周轴突变性引起的。非印迹Prader-Willi/Angelman综合征基因座1（NIPA 1）跨膜蛋白的突变导致HSP的常染色体显性形式（SPG 6）。在这里，我们报告说，转基因（Tg）大鼠表达人类NIPA 1/SPG 6突变的神经元（Thy1.2-hNIPA 1G 106 R）表现出显着的早发性行为和电生理异常。详细的形态学分析揭示了独特的组织病理学结果，包括从轴突和树突末端开始的具有内体特征的管状泡状细胞器的积累，随后在CNS和外周神经中发生多灶性空泡变性。此外，NIPA 1G 106 R突变在脊髓中从老年Tg大鼠的结果在骨形态发生蛋白II型受体表达的增加，这表明其降解受损。这种Thy1.2-hNIPA 1G 106 R Tg大鼠模型可能作为一个有价值的工具，了解内体运输的HSP与骨形态发生蛋白II型受体的异常相互作用的发病机制的一个亚组，以及开发潜在的治疗策略与轴突变性和类似的发病机制的疾病。
Supplemental Digital Content is available in the text. Hereditary spastic paraplegias (HSPs) are characterized by progressive spasticity and weakness in the lower extremities that result from length-dependent central to peripheral axonal degeneration. Mutations in the non-imprinted Prader-Willi/Angelman syndrome locus 1 (NIPA1) transmembrane protein cause an autosomal dominant form of HSP (SPG6). Here, we report that transgenic (Tg) rats expressing a human NIPA1/SPG6 mutation in neurons (Thy1.2-hNIPA1G106R) show marked early onset behavioral and electrophysiologic abnormalities. Detailed morphologic analyses reveal unique histopathologic findings, including the accumulation of tubulovesicular organelles with endosomal features that start at axonal and dendritic terminals, followed by multifocal vacuolar degeneration in both the CNS and peripheral nerves. In addition, the NIPA1G106R mutation in the spinal cord from older Tg rats results in an increase in bone morphogenetic protein type II receptor expression, suggesting that its degradation is impaired. This Thy1.2-hNIPA1G106R Tg rat model may serve as a valuable tool for understanding endosomal trafficking in the pathogenesis of a subgroup of HSP with an abnormal interaction with bone morphogenetic protein type II receptor, as well as for developing potential therapeutic strategies for diseases with axonal degeneration and similar pathogenetic mechanisms.