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Mechanism and role of the intra-axonal Calreticulin translation in response to axonal injury.

ABSTRACT: Following injury, sensory axons locally translate mRNAs that encode proteins needed for the response to injury, locally and through retrograde signaling, and for regeneration. In this study, we addressed the mechanism and role of axotomy-induced intra-axonal translation of the ER chaperone Calreticulin. In vivo peripheral nerve injury increased Calreticulin levels in sensory axons. Using an in vitro model system of sensory neurons amenable to mechanistic dissection we provide evidence that axotomy induces local translation of Calreticulin through PERK (protein kinase RNA-like endoplasmic reticulum kinase) mediated phosphorylation of eIF2? by a mechanism that requires both 5' and 3'UTRs (untranslated regions) elements in Calreticulin mRNA. ShRNA mediated depletion of Calreticulin or inhibition of PERK signaling increased axon retraction following axotomy. In contrast, expression of axonally targeted, but not somatically restricted, Calreticulin mRNA decreased retraction and promoted axon regeneration following axotomy in vitro. Collectively, these data indicate that the intra-axonal translation of Calreticulin in response to axotomy serves to minimize the ensuing retraction, and overexpression of axonally targeted Calreticulin mRNA promotes axon regeneration.

SUBMITTER: Pacheco A

PROVIDER: S-EPMC6909931 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Mechanism and role of the intra-axonal Calreticulin translation in response to axonal injury.

Pacheco Almudena A Merianda Tanuja T TT Twiss Jeffery L JL Gallo Gianluca G

Experimental neurology 20191025

Following injury, sensory axons locally translate mRNAs that encode proteins needed for the response to injury, locally and through retrograde signaling, and for regeneration. In this study, we addressed the mechanism and role of axotomy-induced intra-axonal translation of the ER chaperone Calreticulin. In vivo peripheral nerve injury increased Calreticulin levels in sensory axons. Using an in vitro model system of sensory neurons amenable to mechanistic dissection we provide evidence that axoto ...[more]

PMID: 31669485

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Project description:BackgroundIn coronavirus disease-2019 (COVID-19) patients, there is increasing evidence of neuronal injury by the means of elevated serum neurofilament light chain (sNfL) levels. However, the role of systemic inflammation and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immune response with regard to neuronal injury has not yet been investigated.MethodsIn a prospective cohort study, we recruited patients with mild-moderate (n = 39) and severe (n = 14) COVID-19 and measured sNfL levels, cytokine concentrations, SARS-CoV-2-specific antibodies including neutralizing antibody titers, and cell-mediated immune responses at enrollment and at 28(±7) days. We explored the association of neuro-axonal injury as by the means of sNfL measurements with disease severity, cytokine levels, and virus-specific immune responses.ResultssNfL levels, as an indicator for neuronal injury, were higher at enrollment and increased during follow-up in severely ill patients, whereas during mild-moderate COVID-19, sNfL levels remained unchanged. Severe COVID-19 was associated with increased concentrations of cytokines assessed [interleukin (IL)-6, IL-8, interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α)], higher anti-spike IgG and anti-nucleocapsid IgG concentrations, and increased neutralizing antibody titers compared with mild-moderate disease. Patients with more severe disease had higher counts of defined SARS-CoV-2-specific T cells. Increases in sNfL concentrations from baseline to day 28(±7) positively correlated with anti-spike protein IgG antibody levels and with titers of neutralizing antibodies.ConclusionSevere COVID-19 is associated with increased serum concentration of cytokines and subsequent neuronal injury as reflected by increased levels of sNfL. Patients with more severe disease developed higher neutralizing antibody titers and higher counts of SARS-CoV-2-specific T cells during the course of COVID-19 disease. Mounting a pronounced virus-specific humoral and cell-mediated immune response upon SARS-CoV-2 infection did not protect from neuro-axonal damage as by the means of sNfL levels.

Project description:Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelin-associated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19 (that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the RhoA/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.

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Mechanism and role of the intra-axonal Calreticulin translation in response to axonal injury.

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Mechanism and role of the intra-axonal Calreticulin translation in response to axonal injury.

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