Phosphorylation of collapsin response mediator protein-2 disrupts neuronal maturation in a model of adult neurogenesis: Implications for neurodegenerative disorders

University of California, San Diego
Molecular Neurodegeneration (Impact Factor: 6.56). 09/2011; 6(1):67. DOI: 10.1186/1750-1326-6-67
Source: PubMed


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.

  • Source
    • "We also identified expression changes of the CDK5 phosphorylation target CRMP2 in neurons treated with sAPPalpha. Interestingly, CRMP2 phosphorylation impairs neurite outgrowth, an effect that can be reversed by inhibition of CDK5 [45]. We observed reduced phosphorylation of CRMP2 at the CDK5-dependent phosphorylation site (Ser522) in neurons treated with sAPPalpha. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A growing body of evidence suggests a role for soluble alpha-amyloid precursor protein (sAPPalpha) in pathomechanisms of Alzheimer disease (AD). This cleavage product of APP was identified to have neurotrophic properties. However, it remained enigmatic what proteins, targeted by sAPPalpha, might be involved in such neuroprotective actions. Here, we used high-resolution two-dimensional polyacrylamide gel electrophoresis to analyze proteome changes downstream of sAPPalpha in neurons. We present evidence that sAPPalpha regulates expression and activity of CDK5, a kinase that plays an important role in AD pathology. We also identified the cytoprotective chaperone ORP150 to be induced by sAPPalpha as part of this protective response. Finally, we present functional evidence that the sAPPalpha receptor SORLA is essential to mediate such molecular functions of sAPPalpha in neurons.
    Full-text · Article · Jun 2013 · PLoS ONE
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Lymphocyte migration into the central nervous system is a critical step in the physiopathology of a variety of neurological diseases, including multiple sclerosis and virus-induced neuroinflammation. To better understand the molecular mechanisms involved in cells migration, we focused our studies on collapsin response mediator proteins (CRMPs), a group of phosphoproteins that mediate neural cell motility. There is now evidence that collapsin response mediator protein 2 (CRMP2) plays critical roles in the polarization (uropod formation) of T lymphocytes and their subsequent migration. CRMP2 was known to respond to semaphorin, ephrin and neurotrophin signaling in neurons. The link between the chemokine CXCL12, CRMP2 activity and cell migration has been demonstrated in T lymphocytes. These observations and comparisons of the activity of CRMPs in immune and non-immmune cells are summarized here. The ability of a human retrovirus to enhance lymphocyte migration through the modulation of CRMP2 activity is also discussed. In conclusion, viruses have the ability to manipulate the lymphocyte motility machinery, intensifying neural tissue invasion in infected patients.
    Full-text · Article · Oct 2012 · Cell adhesion & migration
  • [Show abstract] [Hide abstract]
    ABSTRACT: Lanthionine ketimine (LK) is a natural sulfur amino acid metabolite with potent neurotrophic activity. Proteomics indicate that LK interacts with collapsin response mediator protein-2 (CRMP2/DPYSL2/UNC-33), a brain-enriched protein that was shown to regulate cytoskeletal remodeling, neuronal morphology, and synaptic function. To elucidate further the molecular interplay and biological action of LK and UNC-33, we began examining the nervous system of Caenorhabditis elegans nematodes in which both LK concentrations and UNC-33 protein were manipulated. To this end, a cell-permeable LK-ester (LKE) was administered to developing C. elegans engineered to express yellow fluorescent protein (YFP) in cholinergic neurons (strain RM3128) or green fluorescent protein (GFP) in GABAergic neurons (strain CZ1200), and neural morphology was assessed. Fluorescent imaging analyses show that LKE exposure to wild-type animals induced neural commissure outgrowth, crossing over, and bundling in both neurites from GABAergic and cholinergic motor neurons. Additionally, when unc-33(e204) hypomorph mutant nematodes (D389N substitution mutants) were exposed to LKE, both the neuroanatomical defects of incomplete dorsoventral neural commissures and the ventral nerve cord gaps were partially rescued. In contrast, LKE did not rescue ventral nerve cord gaps found in unc-33(mn407) null mutant. Together these data suggest possible functions for LK as a regulator of neuritic elongation, corroborate roles for UNC-33/CRMP2 in the mechanism of LKE activity, and suggest the potential of LKE as a therapeutic molecule for neurological diseases involving CRMP2 dysfunction. © 2013 Wiley Periodicals, Inc.
    No preview · Article · Sep 2013 · Journal of Neuroscience Research
Show more