scholarly journals The Chinese Prescription Wen-Pi-Tang Extract Delays Disease Onset in Amyotrophic Lateral Sclerosis Model Mice While Attenuating the Activation of Glial Cells in the Spinal Cord

2009 ◽  
Vol 32 (3) ◽  
pp. 382-388 ◽  
Author(s):  
Michiko Sekiya ◽  
Takashi Ichiyanagi ◽  
Yasumasa Ikeshiro ◽  
Takako Yokozawa
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Glial Cells ◽  
Disease Onset ◽  
Lateral Sclerosis

Ultrastructural features of aberrant glial cells isolated from the spinal cord of paralytic rats expressing the amyotrophic lateral sclerosis-linked SOD1G93A mutation

2017 ◽  
Vol 370 (3) ◽  
pp. 391-401 ◽  
Author(s):  
Marcie Jiménez-Riani ◽  
Pablo Díaz-Amarilla ◽  
Eugenia Isasi ◽  
Gabriela Casanova ◽  
Luis Barbeito ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Glial Cells ◽  
Aberrant Glial Cells ◽  
Lateral Sclerosis

scholarly journals Motor neuron translatome reveals deregulation of SYNGR4 and PLEKHB1 in mutant TDP-43 amyotrophic lateral sclerosis models

2020 ◽  
Vol 29 (16) ◽  
pp. 2647-2661 ◽  
Author(s):  
Rita F Marques ◽  
Jan B Engler ◽  
Katrin Küchler ◽  
Ross A Jones ◽  
Thomas Lingner ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Symptom Onset ◽  
Rna Binding ◽  
Affinity Purification ◽  
Disease Onset ◽  
Motor Symptom ◽  
Pathological Feature ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is an incurable neurological disease with progressive loss of motor neuron (MN) function in the brain and spinal cord. Mutations in TARDBP, encoding the RNA-binding protein TDP-43, are one cause of ALS, and TDP-43 mislocalization in MNs is a key pathological feature of >95% of ALS cases. While numerous studies support altered RNA regulation by TDP-43 as a major cause of disease, specific changes within MNs that trigger disease onset remain unclear. Here, we combined translating ribosome affinity purification (TRAP) with RNA sequencing to identify molecular changes in spinal MNs of TDP-43–driven ALS at motor symptom onset. By comparing the MN translatome of hTDP-43A315T mice to littermate controls and to mice expressing wild type hTDP-43, we identified hundreds of mRNAs that were selectively up- or downregulated in MNs. We validated the deregulated candidates Tex26, Syngr4, and Plekhb1 mRNAs in an independent TRAP experiment. Moreover, by quantitative immunostaining of spinal cord MNs, we found corresponding protein level changes for SYNGR4 and PLEKHB1. We also observed these changes in spinal MNs of an independent ALS mouse model caused by a different patient mutant allele of TDP-43, suggesting that they are general features of TDP-43-driven ALS. Thus, we identified SYNGR4 and PLEKHB1 to be deregulated in MNs at motor symptom onset in TDP-43-driven ALS models. This spatial and temporal pattern suggests that these proteins could be functionally important for driving the transition to the symptomatic phase of the disease.

scholarly journals Microglia RAGE exacerbates the progression of neurodegeneration within the SOD1G93A murine model of amyotrophic lateral sclerosis in a sex-dependent manner

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Michael MacLean ◽  
Judyta Juranek ◽  
Swetha Cuddapah ◽  
Raquel López-Díez ◽  
Henry H. Ruiz ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Murine Model ◽  
Intercellular Communication ◽  
Cervical Spinal Cord ◽  
Disease Onset ◽  
Lumbar Spinal Cord ◽  
Dependent Manner ◽  
Als Patients ◽  
Lateral Sclerosis

Abstract Background Burgeoning evidence highlights seminal roles for microglia in the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). The receptor for advanced glycation end products (RAGE) binds ligands relevant to ALS that accumulate in the diseased spinal cord and RAGE has been previously implicated in the progression of ALS pathology. Methods We generated a novel mouse model to temporally delete Ager from microglia in the murine SOD1G93A model of ALS. Microglia Ager deficient SOD1G93A mice and controls were examined for changes in survival, motor function, gliosis, motor neuron numbers, and transcriptomic analyses of lumbar spinal cord. Furthermore, we examined bulk-RNA-sequencing transcriptomic analyses of human ALS cervical spinal cord. Results Transcriptomic analysis of human cervical spinal cord reveals a range of AGER expression in ALS patients, which was negatively correlated with age at disease onset and death or tracheostomy. The degree of AGER expression related to differential expression of pathways involved in extracellular matrix, lipid metabolism, and intercellular communication. Microglia display increased RAGE immunoreactivity in the spinal cords of high AGER expressing patients and in the SOD1G93A murine model of ALS vs. respective controls. We demonstrate that microglia Ager deletion at the age of symptomatic onset, day 90, in SOD1G93A mice extends survival in male but not female mice. Critically, many of the pathways identified in human ALS patients that accompanied increased AGER expression were significantly ameliorated by microglia Ager deletion in male SOD1G93A mice. Conclusions Our results indicate that microglia RAGE disrupts communications with cell types including astrocytes and neurons, intercellular communication pathways that divert microglia from a homeostatic to an inflammatory and tissue-injurious program. In totality, microglia RAGE contributes to the progression of SOD1G93A murine pathology in male mice and may be relevant in human disease.

scholarly journals How Degeneration of Cells Surrounding Motoneurons Contributes to Amyotrophic Lateral Sclerosis

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2550
Author(s):  
Roxane Crabé ◽  
Franck Aimond ◽  
Philippe Gosset ◽  
Frédérique Scamps ◽  
Cédric Raoul
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Glial Cells ◽  
Neurological Disorder ◽  
Cellular Network ◽  
Motor System ◽  
Progressive Degeneration ◽  
Brain And Spinal Cord ◽  
The Brain ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by the progressive degeneration of upper and lower motoneurons. Despite motoneuron death being recognized as the cardinal event of the disease, the loss of glial cells and interneurons in the brain and spinal cord accompanies and even precedes motoneuron elimination. In this review, we provide striking evidence that the degeneration of astrocytes and oligodendrocytes, in addition to inhibitory and modulatory interneurons, disrupt the functionally coherent environment of motoneurons. We discuss the extent to which the degeneration of glial cells and interneurons also contributes to the decline of the motor system. This pathogenic cellular network therefore represents a novel strategic field of therapeutic investigation.

scholarly journals The review of the methods to obtain non-neuronal cells to study glial influence on Amyotrophic Lateral Sclerosis pathophysiology at molecular level in vitro

2010 ◽  
Vol 25 (3) ◽  
pp. 281-289 ◽  
Author(s):  
Juliana Milani Scorisa ◽  
Tatiana Duobles ◽  
Gabriela Pintar de Oliveira ◽  
Jessica Ruivo Maximino ◽  
Gerson Chadi
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Primary Cultures ◽  
Neuronal Cells ◽  
Disease Onset ◽  
Wild Type ◽  
Rt Pcr ◽  
Lateral Sclerosis

PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that displays a rapid evolution. Current treatments have failed to revert clinical symptoms because the mechanisms involved in the death of motoneuron are still unknown. Recent publications have put non-neuronal cells, particularly, astrocyte and microglia, in the scenario of pathophisiology of the disease. Animal models for ALS, particularly transgenic mice expressing the human SOD1 gene with a G93A mutation (hSOD1), are available and display the phenotype of the disease at cellular and clinical levels. However, it is a lack of detailed information regarding the methods to study the disease in vitro to better understand the contribution of non-neuronal cells in the onset and progression of the pathology. METHODS: Colonies of Swiss mice and transgenic mice expressing hSOD1 mutation as well as non-transgenic controls (wild-type) were amplified after a genotyping evaluation. Disease progression was followed behaviorally and mortality was registered. Highly purified primary cultures of astrocytes and microglia from mouse spinal cord were obtained. Cells were identified by means of GFAP and CD11B immunocytochemistry. The purity of astroglial and microglial cell cultures was also accompanied by means of Western blot and RT-PCR analyses employing a number of markers. RESULTS: The disease onset was about 105 days and the majority of transgenic mice displayed the disease symptoms by 125 days of age and reached the endpoint 20 days later. A substantial motor weakens was registered in the transgenic mice compared to wild-type at the end point. Immunocytochemical, biochemical and RT-PCR analyses demonstrated a highly purified primary cultures of spinal cord astrocytes and microglia. CONCLUSION: It is possible to achieve highly purified primary cultures of spinal cord astrocytes and microglia to be employed in cellular and molecular analyses of the influence of such non-neuronal cells in the pathophysiology of ALS.

scholarly journals Dual Role of Lysophosphatidic Acid Receptor 2 (LPA2) in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 15 ◽  
Author(s):  
Maria Puigdomenech-Poch ◽  
Anna Martínez-Muriana ◽  
Pol Andrés-Benito ◽  
Isidre Ferrer ◽  
Jerold Chun ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Lysophosphatidic Acid ◽  
Disease Onset ◽  
Neuronal Cell ◽  
Lipid Mediator ◽  
Cell Physiology ◽  
Wide Range ◽  
Lateral Sclerosis

Lysophosphatidic acid (LPA) is a pleiotropic extracellular lipid mediator with many physiological functions that signal through six known G protein-coupled receptors (LPA1–6). In the central nervous system (CNS), LPA mediates a wide range of effects including neural progenitor cell physiology, neuronal cell death, axonal retraction, and inflammation. Since inflammation is a hallmark of most neurological conditions, we hypothesized that LPA could be involved in the physiopathology of amyotrophic lateral sclerosis (ALS). We found that LPA2 RNA was upregulated in post-mortem spinal cord samples of ALS patients and in the sciatic nerve and skeletal muscle of SOD1G93A mouse, the most widely used ALS mouse model. To assess the contribution of LPA2 to ALS, we generated a SOD1G93A mouse that was deficient in Lpar2. This animal revealed that LPA2 signaling accelerates disease onset and neurological decline but, unexpectedly, extended the lifespan. To gain insights into the early harmful actions of LPA2 in ALS, we studied the effects of this receptor in the spinal cord, peripheral nerve, and skeletal muscle of ALS mice. We found that LPA2 gene deletion increased microglial activation but did not contribute to motoneuron death, astrogliosis, degeneration, and demyelination of motor axons. However, we observed that Lpar2 deficiency protected against muscle atrophy. Moreover, we also found the deletion of Lpar2 reduced the invasion of macrophages into the skeletal muscle of SOD1G93A mice, linking LPA2 signaling with muscle inflammation and atrophy in ALS. Overall, these results suggest for the first time that LPA2 contributes to ALS, and its genetic deletion results in protective actions at the early stages of the disease but shortens survival thereafter.

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