Abstract
BackgroundRecent 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.ResultsAbnormal 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.ConclusionsThese 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.
Highlights
Recent studies suggest that the pathogenic process in neurodegenerative disorders may disrupt mature neuronal circuitries and neurogenesis in the adult brain
These results reveal a role for collapsin-response mediator protein-2 (CRMP2) in impaired neuronal maturation mediated by abnormal cyclin-dependent kinase-5 (CDK5) activation, and identify a potential downstream functional mechanism involving microtubule destabilization that could contribute to impaired neuronal maturation during adult neurogenesis in neurodegenerative conditions
CRMP2 phosphorylation is increased in an in vitro model of adult neurogenesis with abnormal CDK5 activation In order to investigate the molecular mechanisms that might contribute to defective adult neurogenesis in neurodegenerative disorders, we utilized a model system of adult neurogenesis, in which activation of CDK5 is induced by virus-mediated overexpression of the CDK5 activator, p35
Summary
Recent studies suggest that the pathogenic process in neurodegenerative disorders may disrupt mature neuronal circuitries and neurogenesis in the adult brain. In addition to the alterations in synaptic plasticity in mature neurons in these disorders, recent studies have uncovered evidence suggesting that the pathogenic process in humans and animal models of AD and HIV in the brain might include dysregulation of adult neurogenesis [9,10,11,12,13,14]. This suggests that neurodegeneration may be characterized by a loss of mature neurons and by a decrease in the generation of new neurons in the neurogenic niches of the adult brain. Mechanisms of neurogenesis in the fetal brain have been extensively studied, less is known about the signaling pathways regulating neurogenesis in the adult nervous system and their role in neurodegenerative disorders
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