Chronic infusion of SOD1G93A astrocyte‐secreted factors induces spinal motoneuron degeneration and neuromuscular dysfunction in healthy rats

Ramírez-Jarquín, Uri Nimrod; Rojas, Fabiola; Zundert, Brigitte van; Tapia, Ricardo

doi:10.1002/jcp.25827

Cited by 20 publications

(11 citation statements)

References 35 publications

(69 reference statements)

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“…AbA-induced neuroinflammation was specific because it was not reproduced by control experiments using transplants of wild-type neonatal microglia or cellfree culture medium. Our results are in agreement with previous studies showing neuroinflammation and motor neuron death induced by spinal cord transplantation of glial-restricted precursors bearing SOD1 G93A [14,17,18]. Further work is needed to determine whether SOD1 G93A AbAs can also induce motor neuron death if transplants are left for longer.…”

Section: Discussionsupporting

confidence: 83%

Focal Transplantation of Aberrant Glial Cells Carrying the SOD1G93A Mutation into Rat Spinal Cord Induces Extensive Gliosis

Ibarburu

Trías²,

Lago³

et al. 2017

Neuroimmunomodulation

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Objective: We aimed to determine the potential of aberrant glial cells (AbAs) isolated from the spinal cord of adult SOD1^G93A symptomatic rats to induce gliosis and neuronal damage following focal transplantation into the lumbar spinal cord of wild-type rats. Methods: AbAs were obtained from the spinal cords of SOD1^G93A symptomatic rats. One hundred thousand cells were injected using a glass micropipette into the lumbar spinal cords (L3-L5) of syngeneic wild-type adult rats. Equal volumes of culture medium or wild-type neonatal microglia were used as controls. Seven days after transplantation, immunohistochemistry analysis was carried out using astrocytic and microglia cell markers. Transplanted SOD1^G93A AbAs were recognized by specific antibodies to human SOD1 (hSOD1) or misfolded human SOD1. Results: Seven days after transplantation, AbAs were mainly detected in the medial region of the lumbar ventral horn as a well-limited cell cluster formed at the site of injection by their immunoreactivity to either misfolded SOD1 or normally folded hSOD1. Compared with controls, transplanted AbAs were surrounded by marked microgliosis and reactive astrocytes. Marked microgliosis was observed to extend bilaterally up to the cervical cord. Motor neurons close to AbA transplants were surrounded by activated glial cells and displayed ubiquitin aggregation. Conclusions: AbAs bearing mutant SOD1^G93A have the potential to induce neuroinflammation along the spinal cord and incipient damage to the motor neurons. The emergence of AbAs during amyotrophic lateral sclerosis pathogenesis may therefore be a mechanism to boost neuroinflammation and spread motor neuron damage along the neuroaxis.

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Section: Discussionsupporting

confidence: 83%

Focal Transplantation of Aberrant Glial Cells Carrying the SOD1G93A Mutation into Rat Spinal Cord Induces Extensive Gliosis

Ibarburu

Trías²,

Lago³

et al. 2017

Neuroimmunomodulation

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“…A similar result was obtained when astrocytes differentiated from ALS patient-derived iPSCs where used for the transplant [80]. Moreover, chronic infusion of conditioned media from hSOD1 G93A -astrocyte cultures induces motor neuron degeneration and neuromuscular dysfunction in wild-type rats [81]. …”

Section: Astrocyte-mediated Motor Neuron Toxicitysupporting

confidence: 55%

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

Pehar

Harlan

Killoy

et al. 2018

CPD

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Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. The molecular mechanism underlying the progressive degeneration of motor neuron remains uncertain but involves a non-cell autonomous process. In acute injury or degenerative diseases astrocytes adopt a reactive phenotype known as astrogliosis. Astrogliosis is a complex remodeling of astrocyte biology and most likely represents a continuum of potential phenotypes that affect neuronal function and survival in an injury-specific manner. In ALS patients, reactive astrocytes surround both upper and lower degenerating motor neurons and play a key role in the pathology. It has become clear that astrocytes play a major role in ALS pathology. Through loss of normal function or acquired new characteristics, astrocytes are able to influence motor neuron fate and the progression of the disease. The use of different cell culture models indicates that ALS-astrocytes are able to induce motor neuron death by secreting a soluble factor(s). Here, we discuss several pathogenic mechanisms that have been proposed to explain astrocyte-mediated motor neuron death in ALS. In addition, examples of strategies that revert astrocyte-mediated motor neuron toxicity are reviewed to illustrate the therapeutic potential of astrocytes in ALS. Due to the central role played by astrocytes in ALS pathology, therapies aimed at modulating astrocyte biology may contribute to the development of integral therapeutic approaches to halt ALS progression.

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“…These anti-or pro-inflammatory phenotypes are neuroprotective or neurotoxic to motor neurons, respectively. Astrocytes, although beneficial to neurons in their resting state, become reactive and contribute to motor neuron death in various models of ALS [3][4][5][6]. Reactive astrocytes have also been shown to impair the process of autophagy in motor neurons, resulting in increased protein aggregation and reduced motor neuron health in in vivo and in vitro models of ALS [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Protocatechuic Acid Extends Survival, Improves Motor Function, Diminishes Gliosis, and Sustains Neuromuscular Junctions in the hSOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by motor neuron apoptosis and subsequent skeletal muscle atrophy caused by oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation. Anthocyanins are polyphenolic compounds found in berries that possess neuroprotective and anti-inflammatory properties. Protocatechuic acid (PCA) is a phenolic acid metabolite of the parent anthocyanin, kuromanin, found in blackberries and bilberries. We explored the therapeutic effects of PCA in a transgenic mouse model of ALS that expresses mutant human Cu, Zn-superoxide dismutase 1 with a glycine to alanine substitution at position 93. These mice display skeletal muscle atrophy, hindlimb weakness, and weight loss. Disease onset occurs at approximately 90 days old and end stage is reached at approximately 120 days old. Daily treatment with PCA (100 mg/kg) by oral gavage beginning at disease onset significantly extended survival (121 days old in untreated vs. 133 days old in PCA-treated) and preserved skeletal muscle strength and endurance as assessed by grip strength testing and rotarod performance. Furthermore, PCA reduced astrogliosis and microgliosis in spinal cord, protected spinal motor neurons from apoptosis, and maintained neuromuscular junction integrity in transgenic mice. PCA lengthens survival, lessens the severity of pathological symptoms, and slows disease progression in this mouse model of ALS. Given its significant preclinical therapeutic effects, PCA should be further investigated as a treatment option for patients with ALS.

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Chronic infusion of SOD1^G93A astrocyte‐secreted factors induces spinal motoneuron degeneration and neuromuscular dysfunction in healthy rats

Cited by 20 publications

References 35 publications

Focal Transplantation of Aberrant Glial Cells Carrying the SOD1<sup>G93A</sup> Mutation into Rat Spinal Cord Induces Extensive Gliosis

Focal Transplantation of Aberrant Glial Cells Carrying the SOD1<sup>G93A</sup> Mutation into Rat Spinal Cord Induces Extensive Gliosis

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

Protocatechuic Acid Extends Survival, Improves Motor Function, Diminishes Gliosis, and Sustains Neuromuscular Junctions in the hSOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

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