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 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 Changes in the concentrations of trimethylamine N-oxide (TMAO) and its precursors in patients with amyotrophic lateral sclerosis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Lu Chen ◽  
Yong Chen ◽  
Mingming Zhao ◽  
Lemin Zheng ◽  
Dongsheng Fan
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Gut Microbiota ◽  
Metabolic Pathway ◽  
Plasma Concentrations ◽  
Disease Onset ◽  
Healthy Controls ◽  
Age And Gender ◽  
And Gender ◽  
Als Patients ◽  
Lateral Sclerosis

Abstract To compare the plasma concentrations of trimethylamine N-oxide (TMAO) and its precursors in amyotrophic lateral sclerosis (ALS) patients, their spouses and healthy controls and to find associations between gut microbiota metabolites and ALS. ALS patients were recruited at Peking University Third Hospital from January 2015 to December 2018. Information was collected from their spouses at the same time. Age and gender matched healthy controls were recruited from individuals who visited the physical examination center for health checkups. Blood samples were collected after at least 4 h of fasting. Concentrations of the metabolites were quantified using stable isotope dilution liquid chromatography–tandem mass spectrometry. Group differences were analyzed using parametric and nonparametric tests, as appropriate. In this study, 160 patients with ALS were recruited. In these patients, 63 were compared with their spouses, 148 were compared with age and gender matched controls, and 60 were compared with both their spouses and heathy controls in the same time. The carnitine concentration was significantly higher in patients than in their spouses, while there were no significant differences in the concentrations of other metabolites. The carnitine and betaine concentrations were higher, while the choline, TMAO and butyrobetaine concentrations were lower in ALS than in healthy controls. The concentrations of the metabolites in the spouses were more similar to the ALS patients rather than to the healthy controls. In the ALS group, the plasma concentrations of carnitine, betaine, choline and TMAO were inversely related to the severity of upper motor neuron impairment. The TMAO metabolic pathway of the gut microbiota is disturbed in both ALS patients and their spouses, which might suggest that the changes in the gut microbiota occurred before disease onset. The negative correlations between the involvement of UMNs and the concentrations of the metabolites might suggest that the inhibition of this metabolic pathway might lead to a better prognosis in ALS patients.

scholarly journals The possible meaning of fractional anisotropy measurement of the cervical spinal cord in correct diagnosis of amyotrophic lateral sclerosis

2015 ◽  
Vol 37 (3) ◽  
pp. 417-421 ◽  
Author(s):  
Slawomir Budrewicz ◽  
Pawel Szewczyk ◽  
Joanna Bladowska ◽  
Ryszard Podemski ◽  
Ewa Koziorowska-Gawron ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Fractional Anisotropy ◽  
Cervical Spinal Cord ◽  
Correct Diagnosis ◽  
Anisotropy Measurement ◽  
Lateral Sclerosis

scholarly journals Early upregulation of cytosolic phospholipase A2α in motor neurons is induced by misfolded SOD1 in a mouse model of amyotrophic lateral sclerosis

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Yafa Fetfet Malada Edelstein ◽  
Yulia Solomonov ◽  
Nurit Hadad ◽  
Leenor Alfahel ◽  
Adrian Israelson ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Motor Neurons ◽  
Dependent Manner ◽  
Mutant Sod1 ◽  
Over Expression ◽  
Cytosolic Phospholipase ◽  
Misfolded Sod1 ◽  
Lateral Sclerosis

Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal multifactorial neurodegenerative disease characterized by the selective death of motor neurons. Cytosolic phospholipase A2 alpha (cPLA2α) upregulation and activation in the spinal cord of ALS patients has been reported. We have previously shown that cPLA2α upregulation in the spinal cord of mutant SOD1 transgenic mice (SOD1G93A) was detected long before the development of the disease, and inhibition of cPLA2α upregulation delayed the disease’s onset. The aim of the present study was to determine the mechanism for cPLA2α upregulation. Methods Immunofluorescence analysis and western blot analysis of misfolded SOD1, cPLA2α and inflammatory markers were performed in the spinal cord sections of SOD1G93A transgenic mice and in primary motor neurons. Over expression of mutant SOD1 was performed by induction or transfection in primary motor neurons and in differentiated NSC34 motor neuron like cells. Results Misfolded SOD1 was detected in the spinal cord of 3 weeks old mutant SOD1G93A mice before cPLA2α upregulation. Elevated expression of both misfolded SOD1 and cPLA2α was specifically detected in the motor neurons at 6 weeks with a high correlation between them. Elevated TNFα levels were detected in the spinal cord lysates of 6 weeks old mutant SOD1G93A mice. Elevated TNFα was specifically detected in the motor neurons and its expression was highly correlated with cPLA2α expression at 6 weeks. Induction of mutant SOD1 in primary motor neurons induced cPLA2α and TNFα upregulation. Over expression of mutant SOD1 in NSC34 cells caused cPLA2α upregulation which was prevented by antibodies against TNFα. The addition of TNFα to NSC34 cells caused cPLA2α upregulation in a dose dependent manner. Conclusions Motor neurons expressing elevated cPLA2α and TNFα are in an inflammatory state as early as at 6 weeks old mutant SOD1G93A mice long before the development of the disease. Accumulated misfolded SOD1 in the motor neurons induced cPLA2α upregulation via induction of TNFα.

USP10 inhibits aberrant cytoplasmic aggregation of TDP-43 by promoting stress granule clearance

2022 ◽  
Author(s):  
Masahiko Takahashi ◽  
Hiroki Kitaura ◽  
Akiyoshi Kakita ◽  
Taichi Kakihana ◽  
Yoshinori Katsuragi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Proteasome Inhibitor ◽  
Rna Binding ◽  
Protein Aggregates ◽  
Causative Factor ◽  
Stress Conditions ◽  
Dependent Manner ◽  
Cytoplasmic Protein ◽  
Als Patients ◽  
Lateral Sclerosis

TDP-43 is a causative factor of amyotrophic lateral sclerosis (ALS). Cytoplasmic TDP-43 aggregates in neurons are a hallmark pathology of ALS. Under various stress conditions, TDP-43 localizes sequentially to two cytoplasmic protein aggregates: stress granules (SGs) first, and then aggresomes. Accumulating evidence suggests that delayed clearance of TDP-43-positive SGs is associated with pathological TDP-43 aggregates in ALS. We found that USP10 promotes the clearance of TDP-43-positive SGs in cells treated with proteasome inhibitor, thereby promoting the formation of TDP-43-positive aggresomes, and the depletion of USP10 increases the amount of insoluble TDP-35, a cleaved product of TDP-43, in the cytoplasm. TDP-35 interacted with USP10 in an RNA-binding dependent manner; however, impaired RNA-binding of TDP-35 reduced the localization in SGs and aggresomes and induced USP10-negative TDP-35 aggregates. Immunohistochemistry showed that most of the cytoplasmic TDP-43/TDP-35-aggregates in the neurons of ALS patients were USP10-negative. Our findings suggest that USP10 inhibits aberrant aggregation of TDP-43/TDP-35 in the cytoplasm of neuronal cells by promoting the clearance of TDP-43/TDP-35-positive SGs and facilitating the formation of TDP-43/TDP-35-positive aggresomes.

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