Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease.
Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease.
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DOI：
10.1242/dmm.010942
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发表时间：
2013-05
影响因子：
4.3
通讯作者：
Burgess RW
中科院分区：
文献类型：
--
作者：
Bogdanik LP;Sleigh JN;Tian C;Samuels ME;Bedard K;Seburn KL;Burgess RW
Charcot-Marie-Tooth病（CMT）是一种临床和遗传异质性疾病，其特征是外周轴突变性，随后伴有运动和感觉缺陷。一些CMT基因产物在内体分选和转运到溶酶体中起作用，表明这一细胞途径的缺陷可能是这些疾病的共同致病机制。LRSAM1是参与这一过程的E3泛素连接酶，LRSAM1的突变最近被证明可引起CMT。我们在小鼠中产生了Lrsam1的突变，以创建这种形式的CMT （CMT2P）的动物模型。小鼠Lrsam1在周围神经系统的运动神经元和感觉神经元中大量表达。纯合子和杂合子小鼠的神经肌肉表现基本正常，随着年龄的增长，只有非常轻微的神经病变表型。然而，Lrsam1突变小鼠对丙烯酰胺的攻击更敏感，丙烯酰胺是一种导致轴突变性的神经毒性物质，这表明突变小鼠的轴突确实受到损害。在转染的细胞中，LRSAM1主要定位于高尔基体以外的核周腔室中，并且很少与内核体到溶酶体运输途径的组分共定位，这表明其他细胞机制也值得考虑。
Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous condition characterized by peripheral axon degeneration with subsequent motor and sensory deficits. Several CMT gene products function in endosomal sorting and trafficking to the lysosome, suggesting that defects in this cellular pathway might present a common pathogenic mechanism for these conditions. LRSAM1 is an E3 ubiquitin ligase that is implicated in this process, and mutations in LRSAM1 have recently been shown to cause CMT. We have generated mouse mutations in Lrsam1 to create an animal model of this form of CMT (CMT2P). Mouse Lrsam1 is abundantly expressed in the motor and sensory neurons of the peripheral nervous system. Both homozygous and heterozygous mice have largely normal neuromuscular performance and only a very mild neuropathy phenotype with age. However, Lrsam1 mutant mice are more sensitive to challenge with acrylamide, a neurotoxic agent that causes axon degeneration, indicating that the axons in the mutant mice are indeed compromised. In transfected cells, LRSAM1 primarily localizes in a perinuclear compartment immediately beyond the Golgi and shows little colocalization with components of the endosome to lysosome trafficking pathway, suggesting that other cellular mechanisms also merit consideration.
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影响因子：
9.8
作者：
Senderek, J;Bergmann, C;Zerres, K
通讯作者：
Zerres, K
LRR和环域蛋白LRSAM1是一种E3连接酶，对于细胞内沙门氏菌的泛素依赖性自噬至关重要。
影响因子：
30.3
作者：
Huett A;Heath RJ;Begun J;Sassi SO;Baxt LA;Vyas JM;Goldberg MB;Xavier RJ
通讯作者：
Xavier RJ
影响因子：
5.3
作者：
Ewaleifoh, Osefame;Minh Trinh;Griffin, John W.;Thien Nguyen
通讯作者：
Thien Nguyen
影响因子：
16.2
作者：
Fuerst, Peter G.;Bruce, Freyja;Tian, Miao;Wei, Wei;Elstrott, Justin;Feller, Maria B.;Erskine, Lynda;Singer, Joshua H.;Burgess, Robert W.
通讯作者：
Burgess, Robert W.
影响因子：
3.3
作者：
McDonald, Bethan;Martin-Serrano, Juan
通讯作者：
Martin-Serrano, Juan