Axotomy‐induced target disconnection promotes an additional death mechanism involved in motoneuron degeneration in amyotrophic lateral sclerosis transgenic mice

Haulcomb, Melissa M.; Mesnard, Nichole A.; Batka, Richard J.; Alexander, Thomas D.; Sanders, Virginia M.; Jones, Kathryn J.

doi:10.1002/cne.23538

Cited by 13 publications

(46 citation statements)

References 110 publications

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“…Collectively, the contrasting injury-induced responses of FMN vs the surrounding microenvironment within the facial nucleus suggests that there may be a dysregulation of nonneuronal cells following target disconnection that is pro-inflammatory in nature and perhaps contributory to the MN degeneration seen in the mSOD1 mouse model of ALS. Further use of laser capture microdissection to explore gene expression in the facial nucleus of mSOD1 mice, relative to WT, following axotomy-induced target disconnection provided evidence in support of a regenerative FMN phenotype surrounded by a pro-inflammatory environment with the CNS of mSOD1 mice (Mesnard et al 2011; Haulcomb et al 2014). …”

Section: Use Of Axotomy As Tool In Understanding Als Pathogenesismentioning

confidence: 99%

“…The response to peripheral axotomy resembles the axonal die-back response, as both processes result in axonal disconnection from neuromuscular junctions in target muscle and after presynaptic stripping in the CNS. We, therefore, used axotomy as an investigative tool to delineate underlying molecular mechanisms that result in MN degeneration in pre-symptomatic mSOD1 mice (Mesnard et al 2010, 2011, 2013; Haulcomb et al 2014; Mesnard-Hoaglin et al 2014). The superimposition of facial nerve axotomy on pre-symptomatic mice allowed us to experimentally produce simultaneous die-back of a select MN population at a set time and for a controlled length of time post-axotomy.…”

Section: Use Of Axotomy As Tool In Understanding Als Pathogenesismentioning

confidence: 99%

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CD4 + T Cells and Neuroprotection: Relevance to Motoneuron Injury and Disease

Jones

Lovett-Racke

Walker

et al. 2015

J Neuroimmune Pharmacol

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We have established a physiologically relevant mechanism of CD4+ T cell-mediated neuroprotection involving axotomized wildtype (WT) mouse facial motoneurons (FMN) with significance in the treatment of amyotrophic lateral sclerosis (ALS), a fatal MN disease. Use of the transgenic mouse model of ALS involving expression of human mutant superoxide dismutase genes (SOD1G93A; abbreviated here as mSOD1) has accelerated basic ALS research. Superimposition of facial nerve axotomy (FNA) on the mSOD1 mouse during pre-symptomatic stages indicates that they behave like immunodeficient mice in terms of increased FMN loss and decreased functional recovery, through a mechanism that, paradoxically, is not inherent within the MN itself, but, instead, involves a defect in peripheral immune: CNS glial cell interactions. Our goal is to utilize our WT mouse model of immune-mediated neuroprotection after FNA as a template to elucidate how a malfunctioning peripheral immune system contributes to motoneuron cell loss in the mSOD1 mouse. This review will discuss potential immune defects in ALS, as well as provide an up-to-date understanding of how the CD4+ effector T cells provide neuroprotection to motoneurons through regulation of the central microglial and astrocytic response to injury. We will discuss an IL-10 cascade within the facial nucleus that requires a functional CD4+ T cell trigger for activation. The review will discuss the role of T cells in ALS, and our recent reconstitution experiments utilizing our model of T cell-mediated neuroprotection in WT vs mSOD1 mice after FNA. Identification of defects in neural:immune interactions could provide targets for therapeutic intervention in ALS.

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Section: Use Of Axotomy As Tool In Understanding Als Pathogenesismentioning

confidence: 99%

Section: Use Of Axotomy As Tool In Understanding Als Pathogenesismentioning

confidence: 99%

CD4 + T Cells and Neuroprotection: Relevance to Motoneuron Injury and Disease

Jones

Lovett-Racke

Walker

et al. 2015

J Neuroimmune Pharmacol

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“…In addition, a variety of treatments can be implemented, such as applying drugs to the nerve stump 14 , injecting medicines systemically 30 , or even performing cell transfers 31 . Motoneuron diseases such as amyotrophic lateral sclerosis can also be studied using the facial nerve axotomy model 32 . Ongoing applications of this technique involve studying nerve reconnection strategies after transection and the application of pharmaceutical agents to accelerate nerve regeneration after injury.…”

Section: Discussionmentioning

confidence: 99%

Facial Nerve Axotomy in Mice: A Model to Study Motoneuron Response to Injury

Olmstead

Mesnard-Hoaglin

Batka

et al. 2015

JoVE

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The goal of this surgical protocol is to expose the facial nerve, which innervates the facial musculature, at its exit from the stylomastoid foramen and either cut or crush it to induce peripheral nerve injury. Advantages of this surgery are its simplicity, high reproducibility, and the lack of effect on vital functions or mobility from the subsequent facial paralysis, thus resulting in a relatively mild surgical outcome compared to other nerve injury models. A major advantage of using a cranial nerve injury model is that the motoneurons reside in a relatively homogenous population in the facial motor nucleus in the pons, simplifying the study of the motoneuron cell bodies. Because of the symmetrical nature of facial nerve innervation and the lack of crosstalk between the facial motor nuclei, the operation can be performed unilaterally with the unaxotomized side serving as a paired internal control. A variety of analyses can be performed postoperatively to assess the physiologic response, details of which are beyond the scope of this article. For example, recovery of muscle function can serve as a behavioral marker for reinnervation, or the motoneurons can be quantified to measure cell survival. Additionally, the motoneurons can be accurately captured using laser microdissection for molecular analysis. Because the facial nerve axotomy is minimally invasive and well tolerated, it can be utilized on a wide variety of genetically modified mice. Also, this surgery model can be used to analyze the effectiveness of peripheral nerve injury treatments. Facial nerve injury provides a means for investigating not only motoneurons, but also the responses of the central and peripheral glial microenvironment, immune system, and target musculature. The facial nerve injury model is a widely accepted peripheral nerve injury model that serves as a powerful tool for studying nerve injury and regeneration. Video LinkThe video component of this article can be found at

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“…Interestingly, while axotomized SOD1 G93A FMN respond with a pro-regenerative response similar to WT, a dysregulated response to axotomy exists in the microenvironment surrounding the SOD1 G93A FMN cell bodies (Mesnard et al, 2011). Importantly, target disconnection via disease or facial nerve axotomy in SOD1 G93A mice results in comparable motoneuron- and glial-specific molecular changes within the facial nucleus (Haulcomb et al, 2014). Furthermore, SOD1 G93A FMN exhibit a delayed functional recovery response to facial nerve crush axotomy, relative to WT mice (Mesnard et al, 2013), that resembles the delayed functional recovery response of FMN in immunodeficient mice following facial nerve crush (Serpe et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

SOD1G93A transgenic mouse CD4+ T cells mediate neuroprotection after facial nerve axotomy when removed from a suppressive peripheral microenvironment

Mesnard-Hoaglin

Xin

Haulcomb

et al. 2014

Brain, Behavior, and Immunity

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving motoneuron (MN) axonal withdrawal and cell death. Previously, we established that facial MN (FMN) survival levels in the SOD1G93A transgenic mouse model of ALS are reduced and nerve regeneration is delayed, similar to immunodeficient RAG2-/- mice, after facial nerve axotomy. The objective of this study was to examine the functionality of SOD1G93A splenic microenvironment, focusing on CD4+ T cells, with regard to defects in immune-mediated neuroprotection of injured MN. We utilized the RAG2-/- and SOD1G93A mouse models, along with the facial nerve axotomy paradigm and a variety of cellular adoptive transfers, to assess immune-mediated neuroprotection of FMN survival levels. We determined that adoptively transferred SOD1G93A unfractionated splenocytes into RAG2-/- mice were unable to support FMN survival after axotomy, but that adoptive transfer of isolated SOD1G93A CD4+ T cells could. Although WT unfractionated splenocytes adoptively transferred into SOD1G93A mice were able to maintain FMN survival levels, WT CD4+ T cells alone could not. Importantly, these results suggest that SOD1G93A CD4+ T cells retain neuroprotective functionality when removed from a dysfunctional SOD1G93A peripheral splenic microenvironment. These results also indicate that the SOD1G93A central nervous system microenvironment is able to re-activate CD4+ T cells for immune-mediated neuroprotection when a permissive peripheral microenvironment exists. We hypothesize that dysfunctional SOD1G93A peripheral splenic microenvironment may compromise neuroprotective CD4+ T cell activation and/or differentiation, which, in turn, results in impaired immune-mediated neuroprotection for MN survival after peripheral axotomy in SOD1G93A mice.

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Axotomy‐induced target disconnection promotes an additional death mechanism involved in motoneuron degeneration in amyotrophic lateral sclerosis transgenic mice

Cited by 13 publications

References 110 publications

CD4 + T Cells and Neuroprotection: Relevance to Motoneuron Injury and Disease

CD4 + T Cells and Neuroprotection: Relevance to Motoneuron Injury and Disease

Facial Nerve Axotomy in Mice: A Model to Study Motoneuron Response to Injury

SOD1G93A transgenic mouse CD4+ T cells mediate neuroprotection after facial nerve axotomy when removed from a suppressive peripheral microenvironment

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