Collapsing Response Mediator Protein Research Articles

Uncoupling the CRMP2-CaV2.2 Interaction Reduces Pain-Like Behavior in a Preclinical Joint-Pain Model

Osteoarthritis (OA) represents a significant pain challenge globally, as current treatments are limited and come with substantial and adverse side effects. Voltage-gated calcium channels have proved to be pharmacologically effective targets, with multiple Food and Drug Administration-approved CaV2.2 modulators available for the treatment of pain. Although effective, drugs targeting CaV2.2 are complicated by the same obstacles facing other pain therapeutics—invasive routes of administration, narrow therapeutic windows, side effects, and addiction potential. We have identified a key regulator of CaV2.2 channels, collapsin response mediator protein 2, that allows us to indirectly regulate CaV2.2 expression and function. We previously developed a peptidomimetic modulator of collapsin response mediator protein 2, CBD3063, that effectively reverses neuropathic and inflammatory pain without negative side effects by reducing membrane expression of CaV2.2. The potent analgesic properties of CBD3063, combined with the lack of negative side effects, prompted us to assess the efficacy of CBD3063 in a rodent model of OA pain. Here, we demonstrate the intraperitoneal administration of CBD3063 alleviates both evoked and nonevoked behavioral hallmarks of OA pain. Further, we reveal that CBD3063 reduces OA-induced increased neural activity in the parabrachial nucleus, a key supraspinal site modulating the pain experience. Together, these studies suggest that CBD3063 is an effective analgesic for OA pain. PerspectiveDespite the high prevalence of OA pain worldwide, current treatment options remain limited. We demonstrate that CBD3063-mediated disruption of the CaV2.2-collapsin response mediator protein 2 interaction alleviates pain in a preclinical joint pain model, providing a promising basis for the development of new OA pain treatments.

Uncoupling the CRMP2-CaV2.2 interaction reduces pain-like behavior in a preclinical osteoarthritis model.

Osteoarthritis (OA) represents a significant pain challenge globally, as current treatments are limited and come with substantial and adverse side effects. Voltage-gated calcium channels have proved to be pharmacologically effective targets, with multiple FDA-approved CaV2.2 modulators available for the treatment of pain. Although effective, drugs targeting CaV2.2 are complicated by the same obstacles facing other pain therapeutics-invasive routes of administration, narrow therapeutic windows, side effects, and addiction potential. We have identified a key regulator of CaV2.2 channels, collapsing response mediator protein 2 (CRMP2), that allows us to indirectly regulate CaV2.2 expression and function. We developed a peptidomimetic modulator of CRMP2, CBD3063, that effectively reverses neuropathic and inflammatory pain without negative side effects by reducing membrane expression of CaV2.2. Using a rodent model of OA, we demonstrate the intraperitoneal administration of CBD3063 alleviates both evoked and non-evoked behavioral hallmarks of OA pain. Further, we reveal that CBD3063 reduces OA-induced increased neural activity in the parabrachial nucleus, a key supraspinal site modulating the pain experience. Together, these studies suggest CBD3063 is an effective analgesic for OA pain.

Brief pup separation during lactation confers resilience in behavioural deficits induced by chronic restraint stress in postpartum C57BL/6J dams.

The postpartum period is a complex time for females that affects health recovery. Stress during this period is one of the main risk factors for depression. Therefore, preventing stress-induced depression in the postpartum period is of great importance. Pup separation (PS) is a natural paradigm of postpartum care; however, the effect of different PS protocols during lactation on stress-induced depressive behaviours in dams is unknown. Lactating C57BL/6J mice were subjected to no pup separation (NPS), brief PS (15 min/day, PS15) or long PS (180 min/day, PS180) from postpartum day 1 to postpartum day 21 and were then subjected to chronic restraint stress (CRS) for 21 days. Behavioural tests, specifically the open field test (OFT), elevated plus maze (EPM) test and tail suspension test (TST), were performed. The expression of mRNA and protein in the hippocampus and microbiota composition were also assessed. We observed CRS-induced anxiety- and depression-like behaviours in NPS dams. In addition, in NPS dams, microglial activation and the levels of NOD-like receptor pyrin domain containing 3, caspase-1 and interleukin-1β were increased, whereas expression levels of collapsing response mediator protein 2 (CRMP2) and α-tubulin were decreased. However, immobility time in the TST was lower in PS15+CRS dams than in NPS+CRS dams, and time spent in the centre during the OFT and in the open arms during the EPM test was higher in PS15+CRS dams, indicating resilience. Expression of hippocampal biomarkers of neuroinflammation was inhibited and levels of CRMP2-mediated neuroplasticity were increased in PS15+CRS dams. Notably, we observed taxonomic changes in the cecal microbiota across different PS groups, as well as relationships between gut microbiota composition and some biomarkers of hippocampal neuroinflammation and neuroplasticity. The sample size for gut microbiota analysis in this study was small. Collectively, the results of this study confirm that brief PS confers stress resilience in CRS-induced behavioural deficits and reverses hippocampal neuroinflammation-neuroplasticity injury and gut microbiota imbalance.

Swimming exercise reverses chronic unpredictable mild stress-induced depression-like behaviors and alleviates neuroinflammation and collapsing response mediator protein-2-mediated neuroplasticity injury in adult male mice.

ObjectiveImpaired neuroplasticity and neuroinflammation are vital in the mechanisms of depression. Exercise alleviates depressive symptoms and ameliorates body functions. Swimming is one of the most common exercises; however, whether swimming alters depressive behaviors and the underlying mechanism has not been fully elucidated.MethodsMale C57/BL6J mice were exposed to chronic unpredictable mild stress (CUMS) for 6 weeks and then were subjected to a 5-week swimming program. Behavioral test, including sucrose preference test (SPT), open field test (OFT), elevated plus-maze (EPM) test, and tail suspension test (TST), was conducted to assess the anxiety-like and depressive behaviors. Western blotting and immunofluorescence staining were carried out after tissue collection.ResultsThis study showed that CUMS-induced depressive behaviors but swimming exercise increased sucrose preference in SPT, increased time and velocity in the center on OFT, decreased time in the closed arm, increased time in the open arm in EPM, and decreased immobility time in TST. We further found swimming exercise increased hippocampal collapsing response mediator protein-2 (CRMP2) expression and decreased p-CRMP2 expression in CUMS mice. CUMS inhibited the levels of α-tubulin and CRMP2, and the expression of ionized calcium-binding adaptor molecule 1 and caspase-1, whereas swimming reversed them in CUMS-exercised mice.ConclusionOur study confirmed that swimming exercise reverses CUMS-induced depressive behaviors, and neuroinflammation and CRMP2-mediated neuroplasticity are involved, which may provide a new insight into the antidepression therapy of exercise.

Edonerpic maleate regulates glutamate receptors through CRMP2- and Arc-mediated mechanisms in response to brain trauma

Dysfunction of ionotropic glutamate receptors (iGluRs) is a key molecular mechanism of excitotoxic neuronal injury following traumatic brain injury (TBI). Edonerpic maleate is a low molecular-weight compound that was screened as a candidate neuroprotective agent. In this study, we investigated its effects on TBI and GluRs signaling. Traumatic neuronal injury (TNI) induced by scratch followed by glutamate treatment was performed to mimic TBI in vitro. Edonerpic maleate at 1 and 10 μM exerted protective activity when it was added within 2 h following injury. The protective activities were also confirmed by the reduction of lipid peroxidation and oxidative stress. In addition, edonerpic maleate inhibited the expression of surface NR2B, total GluR1, and surface GluR1, and mitigated the intracellular Ca2+ responses following injury in vitro. Western blot analysis showed that edonerpic maleate reduced the cleavage of collapsing response mediator protein 2 (CRMP2), but increased the expression of postsynaptic protein Arc. By using gene overexpression and silencing technologies, CRMP2 was overexpressed and Arc was knockdown in cortical neurons. The results showed that the effect of edonerpic maleate on NMDA receptor expression was mediated by CRMP2, whereas the edonerpic maleate-induced AMPA receptor regulation was dependent on Arc activation. In in vivo TBI model, 30 mg/kg edonerpic maleate alleviated the TBI-induced brain edema, neuronal loss, and microglial activation, with no effect on locomotor function at 24 h. However, edonerpic maleate improves long-term neurological function after TBI. Furthermore, edonerpic maleate inhibited CRMP2 cleavage but increased Arc activation in vivo. In summary, our results identify edonerpic maleate as a clinically potent small compound with which to attenuate TBI-related brain damage through regulating GluRs signaling.

GPR3 accelerates neurite outgrowth and neuronal polarity formation via PI3 kinase-mediating signaling pathway in cultured primary neurons

During neuronal development, immature neurons extend neurites and subsequently polarize to form an axon and dendrites. We have previously reported that G protein-coupled receptor 3 (GPR3) levels increase during neuronal development, and that GPR3 has functions in neurite outgrowth and neuronal differentiation in cerebellar granular neurons. Moreover, GPR3 is transported and concentrated at the tips of neurite, thereby contributing to the local activation of protein kinase A (PKA). However, the signaling pathways for GPR3-mediated neurite outgrowth and its subsequent effects on neuronal polarization have not yet been elucidated. We therefore analyzed the signaling pathways related to GPR3-mediated neurite outgrowth, and also focused on the possible roles of GPR3 in axon polarization. We demonstrated that, in cerebellar granular neurons, GPR3-mediated neurite outgrowth was mediated by multiple signaling pathways, including those of PKA, extracellular signal-regulated kinases (ERKs), and most strongly phosphatidylinositol 3-kinase (PI3K). In addition, the GPR3-mediated activation of neurite outgrowth was associated with G protein-coupled receptor kinase 2 (GRK2)-mediated signaling and phosphorylation of the C-terminus serine/threonine residues of GPR3, which affected downstream protein kinase B (Akt) signaling. We further demonstrated that GPR3 was transiently increased early in the development of rodent hippocampal neurons. It was subsequently concentrated at the tip of the longest neurite, and was thus associated with accelerated polarity formation in a PI3K-dependent manner in rat hippocampal neurons. In addition, GPR3 knockout in mouse hippocampal neurons led to delayed neuronal polarity formation, thereby affecting the dephosphorylation of collapsing response mediator protein 2 (CRMP2), which is downstream of the PI3K signaling pathway. Taken together, these findings suggest that the intrinsic expression of GPR3 in differentiated neurons constitutively activates PI3K-mediated signaling pathway predominantly, thus accelerating neurite outgrowth and further augmenting polarity formation in primary cultured neurons.

Phosphorylation of CRMP2 by Cdk5 Negatively Regulates the Surface Delivery and Synaptic Function of AMPA Receptors.

AMPA receptor mediate most fast excitatory synaptic transmission and play a key role in synaptic plasticity in the central nervous system (CNS) by trafficking and targeting of its subunits to individual postsynaptic membrane. Collapsing response mediator protein 2 (CRMP2), an intracellular phospho-protein, has been reported to promote the maturation of the dendritic spine and transfer AMPA receptors to the membrane. However, our knowledge about the molecular mechanisms of CRMP2 regulating AMPA receptors trafficking is limited. Here, we reported that CRMP2 promoted the surface expression of AMPA receptor GluA1 subunit in cultured hippocampal neurons and in HEK293T cells expressing GluA1 subunits. Furthermore, we found that CRMP2 interacted with GluA1, and their interaction was inhibited by CRMP2 phosphorylation at ser522. Moreover, our results showed that phosphorylation of CRMP2 at ser522 by cyclin-dependent kinase 5 (Cdk5) decreased the fluorescence intensity of surface GluA1 and the amplitude and frequency of miniature excitatory synaptic currents (mEPSCs) in cultured hippocampal neurons, indicating a reduction levels and synaptic function of AMPA receptors. Taken together, our data demonstrated that phosphorylation of CRMP2 by Cdk5 is important for AMPA receptor surface delivery in hippocampal neurons.

Molecular Mechanism for PACAP 38-Induced Neurite Outgrowth in PC12 Cells

The present research investigates the molecular mechanism of neurite outgrowth (protrusion elongation) under pituitary adenylate cyclase-activating polypeptide (PACAP) 38 treatments using a rat adrenal-derived pheochromocytoma cell line—PC12. This study specifically looks into the regulation of PACAP38-induced collapsing response mediator protein 2 (CRMP2) previously identified in a mouse brain ischemia model and which could be recovered by PACAP38 treatment. Previously, DNA microarray analysis revealed that PACAP 38-mediated neuroprotection involved not only CRMP2 but also pathways related to glycogen synthase kinase-3β (GSK-3β) and other signaling components. Thus, to clarify whether CRMP2 acts directly on PACAP38 or through GSK-3β as part of the mechanism of PACAP38-induced neurite outgrowth, we observed neurite outgrowth in the presence of GSK-3β inhibitors and activators. PC12 cells were treated with PACAP38 being added to the cell culture medium at concentrations of 10−7 M, 10−8 M, and 10−9 M. Post PACAP38 treatment, immunostaining was used to confirm protrusion elongation of the PC12 cells, while RT-PCR, two-dimensional gel electrophoresis in conjunction with Western blotting, and inhibition experiments were performed to confirm the expression of the PACAP gene, its receptors, and downstream signaling components. Our data show that neurite protrusion elongation by PACAP38 (10−7 M) in PC12 cells is mediated through the PAC1-R receptor as demonstrated by its suppression by a specific inhibitor PA-8. Inhibitor experiments suggested that PACAP38-triggered neurite protrusion follows a GSK-3β-regulated pathway, where the AKT and cAMP/ERK pathways are involved and where the inhibition of Rho/Roc could enhance neurite protrusion under PACAP38 stimulation. Although we could not yet confirm the exact role and position of CRMP2 in PACAP38-mediated PC12 cell elongation, it appears that its phosphorylation and dephosphorylation have a correlation with the neurite protrusion elongation through the interplay of CDK5, which needs to be investigated further.

Dysregulated CRMP Mediates Circadian Deficits in a Drosophila Model of Fragile X Syndrome

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability, resulting from the lack of functional fragile X mental retardation protein (FMRP), an mRNA binding protein mainly serving as a translational regulator. Loss of FMRP leads to dysregulation of target mRNAs. The Drosophila model of FXS show an abnormal circadian rhythm with disruption of the output pathway downstream of the clock network. Yet the FMRP targets involved in circadian regulation have not been identified. Here, we identified collapsing response mediator protein (CRMP) mRNA as a target of FMRP. Knockdown of pan-neuronal CRMP expression ameliorated the circadian defects and abnormal axonal structures of clock neurons (ventral lateral neurons) in dfmr1 mutant flies. Furthermore, specific reduction of CRMP in the downstream output insulin-producing cells attenuated the aberrant circadian behaviors. Molecular analyses revealed that FMRP binds with CRMP mRNA and negatively regulates its translation. Our results indicate that CRMP is an FMRP target and establish an essential role for CRMP in the circadian output in FXS Drosophila.

Cdc42 Facilitates Axonogenesis by Enhancing Microtubule Stabilization in Primary Hippocampal Neurons.

The establishment of polarity is an essential process in early neuronal development. Cdc42, a GTPase of the Rho family, is a key regulator of cytoskeletal dynamics and neuronal polarity. However, the mechanisms underlying the action of cdc42 in regulating axonogenesis have not been elucidated. Here, we expressed wild-type cdc42, a constitutively active cdc42 mutant (cdc42F28L) and a dominant negative cdc42 mutant (cdc42N17), respectively, in the primary hippocampal neurons to alter the activity of cdc42. We found that cdc42 activities were paralleled with the capacities to promote axonogenesis in the cultured neurons. Cdc42 also enhanced microtubule stability in the cultured neurons. Pharmacologically stabilizing microtubules significantly abrogated the defective axonogenesis induced by cdc42 inhibition. Moreover, cdc42 promoted the dephosphorylation of collapsing response mediator protein-2 (CRMP-2) at Thr514 by increasing GSK-3β phosphorylation at Ser9 in the cultured neurons. These findings suggest that cdc42 may facilitate axonogenesis by promoting microtubule stabilization in rat primary hippocampal neurons.

Spastin Interacts with CRMP2 to Regulate Neurite Outgrowth by Controlling Microtubule Dynamics through Phosphorylation Modifications.

Our work aims to revealing the underlying microtubule mechanism of neurites outgrowth during neuronal development and also proposes a feasible intervention pathway for reconstructing neural network connections after nerve injury. Microtubule polymerization and severing form the basis for neurite outgrowth and branch formation. However, the mechanisms that underlie the dynamic instability of microtubules are unclear. Here, we showed that neurite outgrowth mediated by collapsing response mediator protein 2 (CRMP2) can be enhanced by spastin, which had an effect on the severing of microtubule cytoskeleton. To explore whether neurite outgrowth was mediated by coordination of CRMP2 and spastin. Hippocampal neurons were cultured in vitro in 24-well culture plates for 4 days before being used to perform the transfection. Calcium phosphate was used to transfect the CRMP2 and spastin constructs and their control into the neurons. An interaction between CRMP2 and spastin was examined by using pull down, CoIP and immunofluorescence colocalization assays. And immunostaining was also performed to determine the morphology of neurites. We first demonstrated that CRMP2 interacted with spastin to promote neurite outgrowth and branch formation. Then our results identified that CRMP2 interacted with the microtubule- binding domain of spastin via its C-terminus, and deleting these binding sites inhibited neurite outgrowth and branch formation. In addition, we confirmed one phosphorylation site at S210 of spastin in hippocampal neurons. Spastin phosphorylation at S210 failed to alter the binding affinity of CRMP2 but inhibited its binding to microtubules. Further study showed that phosphorylation spastin at S210 inhibited the neurite outgrowth induced by CRMP2 and spastin interaction through downregulation of microtubule-severing activity. Taken together, our data demonstrated that both CRMP2 and spastin interaction and the microtubule-severing activity of spastin were required for neurite outgrowth and branch formation.

Resilience in the LPS-induced acute depressive-like behaviors: Increase of CRMP2 neuroprotection and microtubule dynamics in hippocampus

Depressive-like behaviors occur at 24 h after lipopolysaccharide (LPS) injection, but whether the animals have resilience has not been reported. This study is to explore the existence of resilience in the LPS-induced acute depressive-like behaviors and its biological changes in the neuroprotection and microtubule dynamics. The behavioral tests of Sprague-Dawley male rats, including body weight (BW), sucrose preference test (SPT), forced swimming test (FST) and open field test (OFT), which are used to explore depressive and anxiety-like behaviors, were detected at 24 h after intraperitoneal injection of LPS. In the LPS-induced depression group, body weight and sucrose preference index in SPT were decreased, the immobility time in FST was increased, total distance, time in central zone and frequency of rearing in OFT were decreased. However, there was not any difference in behavioral phenotypes between the resilient animals and the saline control group. The activity of collapsing response mediator protein 2 (CRMP2), which is related to neuronal plasticity and neuroprotection, was increased in resilient rats. The brain-derived neurotrophic factor (BDNF) mRNA expression was also increased. The ratio of Tyr/Acet-tubulin in hippocampus, which is an important marker of microtubule dynamics, was increased without alpha-tubulin. In addition, the expression of CRMP2 and alpha-tubulin in dentate gyrus (DG) region increased in resilient animals, but not in CA1 and CA3 regions. This study firstly confirms the phenomenon of resilience in the LPS-induced acute depressive-like behaviors animal model. CRMP2 neuroprotection and microtubule dynamics in hippocampus are enhanced in this phenomenon of resilience, which may functionally contribute to resilience but need further research.

Neuro-Ophthalmic Features of Autoimmune Encephalitides.

Over the past decade, there has been a remarkable advancement in the understanding of autoimmune etiologies of encephalitis. The first identified generation of paraneoplastic encephalitis tends to occur in older populations, responds poorly to immunotherapy, and is mediated by T-cell damage with antibodies directed toward intracellular antigens. A new generation of autoimmune encephalitides has been described, which are mediated by antibodies to cell-surface proteins, tend to occur in younger individuals, are less frequently associated with malignancy, and often respond better to treatment compared to their intracellular antigen-related paraneoplastic counterparts. This review will focus on several specific antibody-mediated autoimmune encephalitides with neuro-ophthalmic pertinence. Literature review and personal clinical experience. Several of the antibody-mediated encephalitides, specifically N-methyl-D-aspartate receptor, dipeptidyl-peptidase-like protein 6, glial fibrillary acidic protein, metabotropic glutamate receptor 1 (mGluR1), gamma-aminobutyric acid receptor, glutamic acid decarboxylase 65 (GAD65), collapsing response mediator protein 5 (CRMP5), and kelch-like protein 11 (KLHL11), contain features of neuro-ophthalmic interest. The novel cell-surface protein-directed autoimmune encephalitis group can present with a wide range of afferent and efferent neuro-ophthalmic manifestations. Neuro-ophthalmologists should be familiar with these antibody-associated syndromes, which are treatable and often require a high index of suspicion for diagnosis.

Lacosamide intake during pregnancy increases the incidence of foetal malformations and symptoms associated with schizophrenia in the offspring of mice

The use of first and second generation antiepileptic drugs during pregnancy doubles the risk of major congenital malformations and other teratogenic defects. Lacosamide (LCM) is a third-generation antiepileptic drug that interacts with collapsing response mediator protein 2, a protein that has been associated with neurodevelopmental diseases like schizophrenia. The aim of this study was to test the potential teratogenic effects of LCM on developing embryos and its effects on behavioural/histological alterations in adult mice. We administered LCM to pregnant mice, assessing its presence, and that of related compounds, in the mothers’ serum and in embryonic tissues using liquid chromatography coupled to quadrupole/time of flight mass spectrometry detection. Embryo morphology was evaluated, and immunohistochemistry was performed on adult offspring. Behavioural studies were carried out during the first two postnatal weeks and on adult mice. We found a high incidence of embryonic lethality and malformations in mice exposed to LCM during embryonic development. Neonatal mice born to dams treated with LCM during gestation displayed clear psychomotor delay and behavioural and morphological alterations in the prefrontal cortex, hippocampus and amygdala that were associated with behaviours associated with schizophrenia spectrum disorders in adulthood. We conclude that LCM and its metabolites may have teratogenic effects on the developing embryos, reflected in embryonic lethality and malformations, as well as behavioural and histological alterations in adult mice that resemble those presented by patients with schizophrenia.

Fluoxetine exposure for more than 2 days decreases the neuronal plasticity mediated by CRMP2 in differentiated PC12 cells

BackgroundRecent studies indicate that antidepressants treatment restores neuronal plasticity. In contrast, some researchers claim that serotonergic antidepressants, including fluoxetine (FLU), may exacerbate neuronal plasticity, which is contradictory and rarely studied. Since almost those studies exposed cells with drugs for 1–2 days as treatment models of antidepressants, it is possible that FLU exposure for longer periods would have opposite effects on neuronal plasticity. ResultsIn the present study, we examined the effects of FLU exposure (up to 3 days) on the neuronal plasticity in differentiated PC12 cells. The cell viability shown a slight decrease at day 2 (93.5 ± 3.5 %), followed by a highly significant decrease at day 3(71.4 ± 4.4 %). As previously reported, neuronal plasticity was significantly upregulated by FLU exposure at day 1. However, the neurite length, activity-regulated cytoskeleton-associated protein (Arc) and c-Fos mRNA were inhibited with FLU exposure at day 3. Similarly, the expression of tubulin, which play important roles in the neuronal plasticity, was the same result. Furthermore, we found α-tubulin interacted with collapsing response mediator protein 2(CRMP2), which is related to neuronal plasticity, and the regulation of CRMP2 activity influenced the neurite length, Arc, c-Fos and tubulin expression. ConclusionsThe results demonstrated that neuronal plasticity was increased by FLU exposure at day 1, but exposure with FLU for more than 2 days had opposite effect on it. The reduction in neuronal plasticity with FLU exposure for more than 2 days might be involved in some aspects of the therapeutic effect of antidepressant on depression.

Enhanced carbonyl stress induces irreversible multimerization of CRMP2 in schizophrenia pathogenesis.

Enhanced carbonyl stress underlies a subset of schizophrenia, but its causal effects remain elusive. Here, we elucidated the molecular mechanism underlying the effects of carbonyl stress in iPS cells in which the gene encoding zinc metalloenzyme glyoxalase I (GLO1), a crucial enzyme for the clearance of carbonyl stress, was disrupted. The iPS cells exhibited significant cellular and developmental deficits, and hyper-carbonylation of collapsing response mediator protein 2 (CRMP2). Structural and biochemical analyses revealed an array of multiple carbonylation sites in the functional motifs of CRMP2, particularly D-hook (for dimerization) and T-site (for tetramerization), which are critical for the activity of the CRMP2 tetramer. Interestingly, carbonylated CRMP2 was stacked in the multimer conformation by irreversible cross-linking, resulting in loss of its unique function to bundle microtubules. Thus, the present study revealed that the enhanced carbonyl stress stemmed from the genetic aberrations results in neurodevelopmental deficits through the formation of irreversible dysfunctional multimer of carbonylated CRMP2.

Brain-specific Crmp2 deletion leads to neuronal development deficits and behavioural impairments in mice.

Several genome- and proteome-wide studies have associated transcription and translation changes of CRMP2 (collapsing response mediator protein 2) with psychiatric disorders, yet little is known about its function in the developing or adult mammalian brain in vivo. Here we show that brain-specific Crmp2 knockout (cKO) mice display molecular, cellular, structural and behavioural deficits, many of which are reminiscent of neural features and symptoms associated with schizophrenia. cKO mice exhibit enlarged ventricles and impaired social behaviour, locomotor activity, and learning and memory. Loss of Crmp2 in the hippocampus leads to reduced long-term potentiation, abnormal NMDA receptor composition, aberrant dendrite development and defective synapse formation in CA1 neurons. Furthermore, knockdown of crmp2 specifically in newborn neurons results in stage-dependent defects in their development during adult hippocampal neurogenesis. Our findings reveal a critical role for CRMP2 in neuronal plasticity, neural function and behavioural modulation in mice.

Collapsing response mediator protein 2 phosphorylation in neuronal cells is increased in response to proteins released by HTLV-1 infected lymphocytes

Collapsing response mediator protein 2 phosphorylation in neuronal cells is increased in response to proteins released by HTLV-1 infected lymphocytes

Apaf1-deficient cortical neurons exhibit defects in axonal outgrowth.

The establishment of neuronal polarity and axonal outgrowth are key processes affecting neuronal migration and synapse formation, their impairment likely leading to cognitive deficits. Here we have found that the apoptotic protease activating factor 1 (Apaf1), apart from its canonical role in apoptosis, plays an additional function in cortical neurons, where its deficiency specifically impairs axonal growth. Given the central role played by centrosomes and microtubules in the polarized extension of the axon, our data suggest that Apaf1-deletion affects axonal outgrowth through an impairment of centrosome organization. In line with this, centrosomal protein expression, as well as their centrosomal localization proved to be altered upon Apaf1-deletion. Strikingly, we also found that Apaf1-loss affects trans-Golgi components and leads to a robust activation of AMP-dependent protein kinase (AMPK), this confirming the stressful conditions induced by Apaf1-deficiency. Since AMPK hyper-phosphorylation is known to impair a proper axon elongation, our finding contributes to explain the effect of Apaf1-deficiency on axogenesis. We also discovered that the signaling pathways mediating axonal growth and involving glycogen synthase kinase-3β, liver kinase B1, and collapsing-response mediator protein-2 are altered in Apaf1-KO neurons. Overall, our results reveal a novel non-apoptotic role for Apaf1 in axonal outgrowth, suggesting that the neuronal phenotype due to Apaf1-deletion could not only be fully ascribed to apoptosis inhibition, but might also be the result of defects in axogenesis. The discovery of new molecules involved in axonal elongation has a clinical relevance since it might help to explain neurological abnormalities occurring during early brain development.

Year in review 2014: Lung cancer, pleural diseases, respiratory infections and tuberculosis, bronchoscopic intervention and imaging.

Year in review 2014: Lung cancer, pleural diseases, respiratory infections and tuberculosis, bronchoscopic intervention and imaging.