Mutant HSPB1 overexpression in neurons is sufficient to cause age-related motor neuronopathy in mice.
Mutant HSPB1 overexpression in neurons is sufficient to cause age-related motor neuronopathy in mice.
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DOI：
10.1016/j.nbd.2012.03.035
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发表时间：
2012-08
影响因子：
6.1
通讯作者：
Kolb SJ
中科院分区：
文献类型：
--
作者：
Srivastava AK;Renusch SR;Naiman NE;Gu S;Sneh A;Arnold WD;Sahenk Z;Kolb SJ
小热休克蛋白 HSPB1 是一种基于 α-晶状体蛋白的多功能蛋白，已被证明在运动神经元疾病和周围神经损伤的动物模型中具有神经保护作用。 HSPB1 的错义突变导致轴索性腓骨肌萎缩症（CMT2F）和 2 型远端遗传性运动神经病（dHMN-II）。这些疾病的特征是周围神经中运动轴突的选择性丧失，导致远端肌肉无力，并且常常导致严重残疾。为了研究体内运动神经元 HSPB1 突变的致病机制，我们开发并表征了转基因 PrP-HSPB1 和 PrP-HSPB1(R136W) 小鼠。这些小鼠在整个神经系统（包括周围神经的轴突）中表达人类 HSPB1 蛋白。尽管两种小鼠品系均缺乏明显的运动缺陷，但 PrP-HSPB1(R136W) 小鼠出现了年龄依赖性运动轴突病。突变小鼠在脊髓和周围神经中表现出轴突病理，并有证据表明神经丝细胞骨架受损，与细胞器积累相关。伴随这些发现，施密特-兰特曼切口数量增加，作为轴突-雪旺细胞相互作用受损的证据。这些观察结果表明，神经元中 HSPB1(R136W) 的过度表达足以引起小鼠的病理和电生理变化，这些变化在遗传性运动神经病患者中可见。
The small heat shock protein HSPB1 is a multifunctional, α-crystallin-based protein that has been shown to be neuroprotective in animal models of motor neuron disease and peripheral nerve injury. Missense mutations in HSPB1 result in axonal Charcot-Marie-Tooth disease with minimal sensory involvement (CMT2F) and distal hereditary motor neuropathy type 2 (dHMN-II). These disorders are characterized by a selective loss of motor axons in peripheral nerve resulting in distal muscle weakness and often severe disability. To investigate the pathogenic mechanisms of HSPB1 mutations in motor neurons in vivo, we have developed and characterized transgenic PrP-HSPB1 and PrP-HSPB1(R136W) mice. These mice express the human HSPB1 protein throughout the nervous system including in axons of peripheral nerve. Although both mouse strains lacked obvious motor deficits, the PrP-HSPB1(R136W) mice developed an age-dependent motor axonopathy. Mutant mice showed axonal pathology in spinal cord and peripheral nerve with evidence of impaired neurofilament cytoskeleton, associated with organelle accumulation. Accompanying these findings, increases in the number of Schmidt-Lanterman incisures, as evidence of impaired axon-Schwann cell interactions, were present. These observations suggest that overexpression of HSPB1(R136W) in neurons is sufficient to cause pathological and electrophysiological changes in mice that are seen in patients with hereditary motor neuropathy.