A neurotoxic peripherin splice variant in a mouse model of ALS.
A neurotoxic peripherin splice variant in a mouse model of ALS.
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DOI：
10.1083/jcb.200205027
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发表时间：
2003-03-17
影响因子：
7.8
通讯作者：
Mushynski, Walter E
中科院分区：
文献类型：
--
作者：
Robertson, Janice;Doroudchi, Mohammad M;Nguyen, Minh Dang;Durham, Heather D;Strong, Michael J;Shaw, Gerry;Julien, Jean-Pierre;Mushynski, Walter E
外周蛋白是一种神经元中间丝蛋白（nIF），与肌萎缩性侧索硬化症（ALS）患者和过表达突变型超氧化物歧化酶-1 （SOD1G37R）的转基因小鼠运动神经元的病理聚集有关，在转基因小鼠中过表达时可诱导运动神经元的选择性变性。小鼠外周蛋白与其他nIF蛋白相比是独特的，因为三种外周蛋白异构体是通过选择性剪接产生的。本研究在转染细胞系、初级运动神经元以及过表达外周蛋白或过表达SOD1G37R的转基因小鼠中研究了外周蛋白剪接变体Per 58、Per 56和Per 61的特性。在三个亚型中，Per 61被证明具有明显的神经毒性，在培养中不能组装并诱导运动神经元变性。使用同种异型特异性抗体，在SOD1G37R转基因小鼠的运动神经元中检测到Per 61的表达，而在对照组和外周血素转基因小鼠中未检测到。Per 61抗体还选择性地标记了两例家族性ALS患者的运动神经元和轴突球体，并从疾病组织中免疫沉淀出更高分子质量的外周蛋白。这一证据表明，外周蛋白的神经毒性剪接变异体的表达可能与ALS的神经退行性机制有关。
Peripherin, a neuronal intermediate filament (nIF) protein found associated with pathological aggregates in motor neurons of patients with amyotrophic lateral sclerosis (ALS) and of transgenic mice overexpressing mutant superoxide dismutase-1 (SOD1G37R), induces the selective degeneration of motor neurons when overexpressed in transgenic mice. Mouse peripherin is unique compared with other nIF proteins in that three peripherin isoforms are generated by alternative splicing. Here, the properties of the peripherin splice variants Per 58, Per 56, and Per 61 have been investigated in transfected cell lines, in primary motor neurons, and in transgenic mice overexpressing peripherin or overexpressing SOD1G37R. Of the three isoforms, Per 61 proved to be distinctly neurotoxic, being assembly incompetent and inducing degeneration of motor neurons in culture. Using isoform-specific antibodies, Per 61 expression was detected in motor neurons of SOD1G37R transgenic mice but not of control or peripherin transgenic mice. The Per 61 antibody also selectively labeled motor neurons and axonal spheroids in two cases of familial ALS and immunoprecipitated a higher molecular mass peripherin species from disease tissue. This evidence suggests that expression of neurotoxic splice variants of peripherin may contribute to the neurodegenerative mechanism in ALS.