Phosphorylation of collapsin response mediator protein-2 disrupts neuronal maturation in a model of adult neurogenesis: Implications for neurodegenerative disorders.
Phosphorylation of collapsin response mediator protein-2 disrupts neuronal maturation in a model of adult neurogenesis: Implications for neurodegenerative disorders.
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DOI：
10.1186/1750-1326-6-67
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发表时间：
2011-09-24
影响因子：
15.1
通讯作者：
Masliah E
中科院分区：
文献类型：
--
作者：
Crews L;Ruf R;Patrick C;Dumaop W;Trejo-Morales M;Achim CL;Rockenstein E;Masliah E
最近的研究表明，在神经退行性疾病的致病过程可能会破坏成熟的神经元回路和神经发生在成年人的大脑。CDK 5的异常激活与神经退行性疾病有关，最近已经确定CDK 5在成人神经发生中的关键作用。我们已经开发了一种在体外模型的异常CDK 5激活在成年海马神经发生，在这里，我们使用这个模型来调查异常磷酸化下游靶点的CDK 5。成人神经发生体外模型中CDK 5的异常激活导致了降钙素反应介质蛋白-2（CRMP 2）的过度磷酸化和受损的神经突生长。抑制CDK 5或非磷酸化（S522 A）CRMP 2构建体的表达可降低CRMP 2过度磷酸化，并逆转神经突生长缺陷。CRMP 2在微管动力学中起作用;因此，我们使用生化和电子显微镜技术检查了该模型中微管的完整性。我们发现在CDK 5激活的条件下，微管组织被破坏。最后，为了研究这些发现与HIV感染相关的神经退行性疾病中神经发生的相关性，我们对HIV患者和表达HIV-gp 120蛋白的转基因小鼠的大脑进行了免疫化学分析。在HIV脑炎患者和gp 120转基因小鼠的海马中，CDK 5介导的CRMP 2磷酸化显著增加，并且这种效应通过小鼠模型中CDK 5的遗传下调而得以挽救。这些结果揭示了一种涉及微管不稳定的功能机制，通过这种机制，异常的CDK 5活化和CRMP 2过度磷酸化可能导致神经退行性疾病（如HIV脑炎）中的神经发生缺陷。
Recent studies suggest that the pathogenic process in neurodegenerative disorders may disrupt mature neuronal circuitries and neurogenesis in the adult brain. Abnormal activation of CDK5 is associated with neurodegenerative disorders, and recently a critical role for CDK5 in adult neurogenesis has been identified. We have developed an in vitro model of abnormal CDK5 activation during adult hippocampal neurogenesis, and here we used this model to investigate aberrantly phosphorylated downstream targets of CDK5. Abnormal CDK5 activation in an in vitro model of adult neurogenesis results in hyperphosphorylation of collapsin-response mediator protein-2 (CRMP2) and impaired neurite outgrowth. Inhibition of CDK5, or expression of a non-phosphorylatable (S522A) CRMP2 construct reduced CRMP2 hyperphosphorylation, and reversed neurite outgrowth deficits. CRMP2 plays a role in microtubule dynamics; therefore we examined the integrity of microtubules in this model using biochemical and electron microscopy techniques. We found that microtubule organization was disrupted under conditions of CDK5 activation. Finally, to study the relevance of these findings to neurogenesis in neurodegenerative conditions associated with HIV infection, we performed immunochemical analyses of the brains of patients with HIV and transgenic mice expressing HIV-gp120 protein. CDK5-mediated CRMP2 phosphorylation was significantly increased in the hippocampus of patients with HIV encephalitis and in gp120 transgenic mice, and this effect was rescued by genetic down-modulation of CDK5 in the mouse model. These results reveal a functional mechanism involving microtubule destabilization through which abnormal CDK5 activation and CRMP2 hyperphosphorylation might contribute to defective neurogenesis in neurodegenerative disorders such as HIV encephalitis.
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影响因子：
9.8
作者：
Jessberger S;Aigner S;Clemenson GD Jr;Toni N;Lie DC;Karalay O;Overall R;Kempermann G;Gage FH
通讯作者：
Gage FH
影响因子：
64.8
作者：
GOSHIMA, Y;NAKAMURA, F;STRITTMATTER, SM
通讯作者：
STRITTMATTER, SM
影响因子：
21.3
作者：
Fukata, Y;Itoh, TJ;Kaibuchi, K
通讯作者：
Kaibuchi, K
影响因子：
2.9
作者：
Gu, YJ;Hamajima, N;Ihara, Y
通讯作者：
Ihara, Y
影响因子：
4.8
作者：
Hou, Zhibo;Li, Qing;Qi, Robert Z.
通讯作者：
Qi, Robert Z.