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首页> 外文期刊>The European Journal of Neuroscience >Calpain-mediated cleavage of collapsin response mediator protein(CRMP)-2 during neurite degeneration in mice.
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Calpain-mediated cleavage of collapsin response mediator protein(CRMP)-2 during neurite degeneration in mice.

机译：钙蛋白酶介导的小鼠神经突变性过程中胶原蛋白反应介质蛋白（CRMP）-2的裂解。

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Axon or dendrite degeneration involves activation of the ubiquitin-proteasome system, failure to maintain neuritic ATP levels, microtubule fragmentation and a mitochondrial permeability transition that occur independently of the somal death programs. To gain further insight into the neurite degeneration mechanims we have compared two-dimensional gel electrophoresis patterns of neurite proteins from suprior cervical ganglia during degeneration caused by nerve growth factor (NGF) deprivation. We show here that collapsin response mediator protein (CRMP)-2 and CMRP-4 protein patterns were altered during beading formation, an early hallmark of neurite degeneration, prior to neurite fragmentation, the final stage of degeneration. Western blotting using a monoclonal antibody against CRMP-2 shows that the native form (64 kDa) was cleaved to generate a truncated form (58 kDa). No cleavage of CRMP-2 or -4 occurred in NGF-deprived neurites from Wld (s) (Wallerian degeneration slow) mutant mice in which neurite degeneration is markedly delayed. Using different protease inhibitors, purified calpain 1 protein and calpain 1-specific siRNA, we have demonstrated that CRMP-2 is a substrate for calpain 1. Indeed, caplain activity was activated at an early phase of neuronal degeneration in cerebellar granule neurons, and down-regulation of caplain 1 expression suppressed CRMP-2 cleavage. Furthermore, this cleavage occurred after vinblastine treatment or in vitro Wallerian degeneration, suggesting that it represents a common step in the process of dying neurites. CRMP-2 and -4 play a pivotal role in axonal growth and transport, and the C-terminus region of CRMP-2 is essential for its binding to kinesin-1. Hence, this cleavage will render them dysfunctional and subject to autophagic processing associated with beading formation, as evidenced by the finding that the truncated form was localized in the beadings.
机译：轴突或树突变性涉及泛素-蛋白酶体系统的激活，无法维持神经ATP的水平，微管碎裂和线粒体通透性转变，而这些转变与体细胞死亡程序无关。为了进一步了解神经突变性机制，我们比较了神经生长因子（NGF）剥夺引起的变性时颈上神经节神经突蛋白质的二维凝胶电泳图谱。我们在这里显示，胶原蛋白反应介导蛋白（CRMP）-2和CMRP-4蛋白质模式在珠粒形成过程中发生了改变，珠粒形成是神经突变性的早期标志，在神经突碎裂之前是变性的最后阶段。使用针对CRMP-2的单克隆抗体进行的蛋白质印迹显示，天然形式（64 kDa）被切割生成了截短形式（58 kDa）。在明显延迟了神经突变性的Wld（s）（Wallerian变性慢）突变小鼠的NGF剥夺的神经突中，没有发生CRMP-2或-4的切割。使用不同的蛋白酶抑制剂，纯化的钙蛋白酶1蛋白和钙蛋白酶1特异性siRNA，我们已经证明CRMP-2是钙蛋白酶1的底物。确实，在小脑颗粒神经元神经元变性的早期激活了caplain活性，并且向下激活调节caplain 1的表达抑制了CRMP-2的切割。此外，这种裂解发生在长春碱处理或体外Wallerian变性后，这表明它代表了神经突染色过程中的一个共同步骤。 CRMP-2和-4在轴突生长和运输中起着关键作用，而CRMP-2的C末端区域对于其与kinesin-1的结合至关重要。因此，这种切割将使它们功能失调，并经受与珠形成相关的自噬过程，如发现截短形式位于珠中所示。

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