Altered reaction of facial motoneurons to axonal damage in the presymptomatic phase of a murine model of familial amyotrophic lateral sclerosis

Mariotti, Raffaella; Cristino, Luigia; Bressan, Caroline A.; Boscolo, Sabrina; Bentivoglio, Marina

doi:10.1016/s0306-4522(02)00448-7

Cited by 22 publications

(26 citation statements)

References 15 publications

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“…A widely used transgenic mouse model of ALS, involving the overexpression of human mutant superoxide dismutase-1 (SOD1 G93A ; abbreviated to mSOD1 in this review), develops disease pathology similar to that in familial and sporadic ALS patients (Gurney et al 1994). Mariotti et al demonstrated increased mSOD1 mouse FMN susceptibility to axotomy-induced cell death (Mariotti et al 2002). The demonstration that axotomy increases cell loss in the animal model of ALS suggests that an additional central nervous system (CNS) pathology, beyond the initiating axonal die-back events, may contribute to differential axotomy-induced target deprivation responses.…”

Section: Introductionmentioning

confidence: 99%

“…The demonstration that axotomy increases cell loss in the animal model of ALS suggests that an additional central nervous system (CNS) pathology, beyond the initiating axonal die-back events, may contribute to differential axotomy-induced target deprivation responses. To explore the differences in response to axotomy by mSOD1 and WT mice, we extended the findings of Mariotti et al (Mariotti et al 2002) by superimposing facial nerve axotomy on pre-symptomatic mSOD1 mice and examining the molecular responses of both axotomized FMN and the surrounding microenvironment in the facial nucleus. In this review, we will summarize the use of axotomy as a tool to understand ALS pathogenesis in the mSOD1 mouse model.…”

Section: Introductionmentioning

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: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…Coupled with evidence indicating decreased levels of FMN survival in presymptomatic mSOD1 mice (Mariotti et al ., 2002), we hypothesized that CD4 + T cells promote motoneuron survival in a mSOD1 mouse model. Recent studies have validated this hypothesis, demonstrating a positive role for CD4 + T cells during mSOD1-mediated disease progression (Beers et al ., 2008), as well as a profound and progressive immunodeficiency that is linked to T cell dysfunction (Banerjee et al ., 2008).…”

Section: Discussionmentioning

confidence: 71%

Effects of facial nerve axotomy on Th2- and Th1-associated chemokine expression in the facial motor nucleus of wild-type and presymptomatic mSOD1 mice

Wainwright

Xin

Mesnard

et al. 2009

Journal of Neuroimmunology

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We have previously demonstrated a neuroprotective mechanism of facial motoneuron (FMN) survival after facial nerve axotomy that is dependent on CD4+ Th2 cell interaction with peripheral antigen-presenting cells, as well as CNS resident microglia. To investigate this mechanism, we chose to study the Th2-associated chemokine, CCL11, and Th1-associated chemokine, CXCL11, in wild type and presymptomatic mSOD1 mice after facial nerve axotomy. In this report, the results indicate that CCL11 is constitutively expressed in the uninjured facial motor nucleus, but CXCL11 is not expressed at all. Facial nerve axotomy induced a shift in CCL11 expression from FMN to astrocytes, whereas CXCL11 was induced in FMN. Differences in the number of CCL11- and CXCL11-expressing cells were observed between WT and mSOD1 mice after facial nerve axotomy.

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“…3 Other studies have suggested that motor neuron cell death is also increased after facial axotomy. 4 Interestingly, axotomy of either the L5 ventral root or sciatic nerve in mutant SOD1-transgenic mice has been reported to actually slow the progression of disease and result in a slowing of motor neuron loss. 5 After crush injury of the sciatic nerve in which the integrity of the nerve was not compromised and regeneration was allowed to occur, it appeared that motor neuron loss was more dramatic on the side of crush injury and was accompanied by an acceleration of disease appearance.…”

Section: Discussionmentioning

confidence: 99%

Amyotrophic Lateral Sclerosis Presenting With a Clivus Mass and Dysarthria

Maragakis

Pardo

2006

Journal of Clinical Neuromuscular Disease

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A patient developed dysarthria and was found to have fibrous dysplasia of the clivus accompanied by cranial nerve impingement, particularly the hypoglossal canal. The dysarthria progressed to more severe bulbar dysfunction and a subsequent diagnosis of amyotrophic lateral sclerosis. This case highlights a discussion of the potential influences of focal lesions on the site of symptom onset in this neurodegenerative disease.A 41-year-old right-handed man presented with dysarthria, dysphagia, and weight loss. Examination initially showed mild tongue atrophy with fasciculations and dysarthria but no significant limb weakness or upper motor neuron findings. The patient underwent magnetic resonance imaging (MRI) of the brain that revealed a mass in the clivus with potential impingement on cranial nerves IX-XII ( Figure 1). Biopsy of this mass was consistent with fibrous dysplasia without evidence of malignancy, and resection was not performed. Over the next year, he developed slowly progressing dysarthria and dysphagia accompanied by dyspnea with mild exertion. This was followed by right upper limb weakness. He never developed diplopia, sensory symptoms, or bowel or bladder incontinence. His family history was notable for a maternal first cousin who died at 50 years of age from amyotrophic lateral sclerosis (ALS) with an initial presentation of difficulty with ambulation. Neither of the patient's parents had similar symptoms.Neurological examination 1 year after the onset of symptoms showed an intact mental status. His speech was profoundly dysarthric, but his language was fluent. Cranial nerve exam was notable for bifacial weakness. His tongue was atrophic with fasciculations bilaterally. Motor examination showed weakness of neck flexion and asymmetric weakness in the upper limbs. Specifically, MRC grade for neck flexion strength was 4; deltoids were 4+ right and 5 left; biceps were 4+ bilaterally; triceps were 4 right and 4+ left; wrist extensors were 4 bilaterally; intrinsic muscles of the hand were 5 on the right and 5 on the left; thumb flexion was 4 bilaterally; hip flexion was 5 bilaterally; leg extension was 5 bilaterally; foot dorsiflexion and plantar flexion were 5 bilaterally. Deep tendon reflexes: jaw jerk was slightly increased. Biceps reflexes were 3 bilaterally; triceps were 2 bilaterally; patellar reflexes were 3 bilaterally. He had crossed adductors. Ankle jerk reflexes were 2 bilaterally. His plantar response was flexor. He had reduced tone in the upper limbs. This was accompanied by atrophy of both upper limbs, most notably in deltoid muscles. He had fasciculations in the cervical paraspinous muscles, trapezius, multiple muscles in the arms, and the quadriceps muscles bilaterally. Sensory examination was intact. Coordination was intact to finger-nosefinger and heel-to-shin testing. He did not have a Romberg sign, and gait exam demonstrated normal toe-heel and tandem gait.Laboratory analysis consisted of a normal cerebrospinal fluid analysis. Cervical spine MRI demonstrated mild cervical spondylosis. ...

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Altered reaction of facial motoneurons to axonal damage in the presymptomatic phase of a murine model of familial amyotrophic lateral sclerosis

Cited by 22 publications

References 15 publications

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

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

Effects of facial nerve axotomy on Th2- and Th1-associated chemokine expression in the facial motor nucleus of wild-type and presymptomatic mSOD1 mice

Amyotrophic Lateral Sclerosis Presenting With a Clivus Mass and Dysarthria

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