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 LanCL1 promotes motor neuron survival and extends the lifespan of amyotrophic lateral sclerosis mice

2019 ◽  
Vol 27 (4) ◽  
pp. 1369-1382 ◽  
Author(s):  
Honglin Tan ◽  
Mina Chen ◽  
Dejiang Pang ◽  
Xiaoqiang Xia ◽  
Chongyangzi Du ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neuronal Survival ◽  
Disease Onset ◽  
Alternative Mechanism ◽  
Specific Expression ◽  
Motor Neuron Survival ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Improving neuronal survival in ALS remains a significant challenge. Previously, we identified Lanthionine synthetase C-like protein 1 (LanCL1) as a neuronal antioxidant defense gene, the genetic deletion of which causes apoptotic neurodegeneration in the brain. Here, we report in vivo data using the transgenic SOD1G93A mouse model of ALS indicating that CNS-specific expression of LanCL1 transgene extends lifespan, delays disease onset, decelerates symptomatic progression, and improves motor performance of SOD1G93A mice. Conversely, CNS-specific deletion of LanCL1 leads to neurodegenerative phenotypes, including motor neuron loss, neuroinflammation, and oxidative damage. Analysis reveals that LanCL1 is a positive regulator of AKT activity, and LanCL1 overexpression restores the impaired AKT activity in ALS model mice. These findings indicate that LanCL1 regulates neuronal survival through an alternative mechanism, and suggest a new therapeutic target in ALS.

scholarly journals RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1

2015 ◽  
Vol 35 (14) ◽  
pp. 2385-2399 ◽  
Author(s):  
Nadine Bakkar ◽  
Arianna Kousari ◽  
Tina Kovalik ◽  
Yang Li ◽  
Robert Bowser
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Antioxidant Response ◽  
Cytoplasmic Inclusions ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons. Various factors contribute to the disease, including RNA binding protein dysregulation and oxidative stress, but their exact role in pathogenic mechanisms remains unclear. We have recently linked another RNA binding protein, RBM45, to ALS via increased levels of protein in the cerebrospinal fluid of ALS patients and its localization to cytoplasmic inclusions in ALS motor neurons. Here we show RBM45 nuclear exit in ALS spinal cord motor neurons compared to controls, a phenotype recapitulatedin vitroin motor neurons treated with oxidative stressors. We find that RBM45 binds and stabilizes KEAP1, the inhibitor of the antioxidant response transcription factor NRF2. ALS lumbar spinal cord lysates similarly show increased cytoplasmic binding of KEAP1 and RBM45. Binding of RBM45 to KEAP1 impedes the protective antioxidant response, thus contributing to oxidative stress-induced cellular toxicity. Our findings thus describe a novel link between a mislocalized RNA binding protein implicated in ALS (RBM45) and dysregulation of the neuroprotective antioxidant response seen in the disease.

scholarly journals A Comprehensive Profile of ChIP-Seq-Based Olig2 Target Genes in Motor Neuron Progenitor Cells Suggests the Possible Involvement of Olig2 in the Pathogenesis of Amyotrophic Lateral Sclerosis

2015 ◽  
Vol 7 ◽  
pp. JCNSD.S23210 ◽  
Author(s):  
Jun-Ichi Satoh ◽  
Naohiro Asahina ◽  
Shouta Kitano ◽  
Yoshihiro Kino
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Progenitor Cells ◽  
Motor Neurons ◽  
Target Genes ◽  
Molecular Networks ◽  
Bhlh Transcription Factor ◽  
Wide Range ◽  
Lateral Sclerosis

Background Amyotrophic lateral sclerosis (ALS) is an intractable neurodegenerative disease that primarily affects motor neurons in the cerebral cortex and the spinal cord. Recent evidence indicates that dysfunction of oligodendrocytes is implicated in the pathogenesis of ALS. The basic helix–loop–helix (bHLH) transcription factor Olig2 plays a pivotal role in the development of both motor neurons and oligodendrocytes in the progenitor of motor neuron (pMN) domain of the spinal cord, supporting evidence for the shared motor neuron/oligodendrocyte lineage. However, a comprehensive profile of Olig2 target genes in pMNs and oligodendrocyte progenitor cells (OPCs) with relevance to the pathogenesis of ALS remains to be characterized. Methods By analyzing the ChIP-Seq datasets numbered SRP007566 and SRP015333 with the Strand NGS program, we identified genome-wide Olig2 target genes in pMNs and OPCs, followed by molecular network analysis using three distinct bioinformatics tools. Results We identified 5966 Olig2 target genes in pMNs, including Nkx2.2, Pax6, Irx3, Ngn2, Zep2 (Cip1), Trp3, Mnx1 (Hb9), and Cdkn1a, and 1553 genes in OPCs. The genes closely related to the keyword “alternative splicing” were enriched in the set of 740 targets overlapping between pMNs and OPCs. Furthermore, approximately one-third of downregulated genes in purified motor neurons of presymptomatic mutant SOD1 transgenic mice and in lumbar spinal cord tissues of ALS patients corresponded to Olig2 target genes in pMNs. Molecular networks of Olig2 target genes indicate that Olig2 regulates a wide range of genes essential for diverse neuronal and glial functions. Conclusions These observations lead to a hypothesis that aberrant regulation of Olig2 function, by affecting biology of both motor neurons and oligodendrocytes, might be involved in the pathogenesis of ALS.

scholarly journals Resveratrol Ameliorates Motor Neuron Degeneration and Improves Survival in SOD1G93AMouse Model of Amyotrophic Lateral Sclerosis

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Lin Song ◽  
Liang Chen ◽  
Xiaojie Zhang ◽  
Jia Li ◽  
Weidong Le
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Neuroprotective Effect ◽  
Disease Onset ◽  
Succinic Dehydrogenase ◽  
Immunofluorescent Staining ◽  
Nissl Staining ◽  
Apoptotic Pathway ◽  
Resveratrol Treatment ◽  
Lateral Sclerosis

Resveratrol has recently been used as a supplemental treatment for several neurological and nonneurological diseases. It is not known whether resveratrol has neuroprotective effect on amyotrophic lateral sclerosis (ALS). To assess the effect of resveratrol on the disease, we tested this agent on an ALS model ofSOD1G93Atransgenic mouse. Rotarod measurement was performed to measure the motor function of the ALS mice. Nissl staining and SMI-32 immunofluorescent staining were used to determine motor neurons survival in the spinal cord of the ALS mice. Hematoxylin-eosin (H&E), succinic dehydrogenase (SDH), and cytochrome oxidase (COX) staining were applied to pathologically analyze the skeletal muscles of the ALS mice. We found that resveratrol treatment significantly delayed the disease onset and prolonged the lifespan of the ALS mice. Furthermore, resveratrol treatment attenuated motor neuron loss, relieved muscle atrophy, and improved mitochondrial function of muscle fibers in the ALS mice. In addition, we demonstrated that resveratrol exerted these neuroprotective effects mainly through increasing the expression of Sirt1, consequently suppressing oxidative stress and downregulating p53 and its related apoptotic pathway. Collectively, our findings suggest that resveratrol might provide a promising therapeutic intervention for ALS.

Amyotrophic Lateral Sclerosis

2019 ◽  
pp. 664-669
Author(s):  
Jennifer M. Martinez-Thompson ◽  
Nathan P. Staff
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Symptom Onset ◽  
Muscle Wasting ◽  
Neurodegenerative Disorder ◽  
Peak Incidence ◽  
Respiratory Involvement ◽  
Sporadic Als ◽  
Bulbar Dysfunction ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disorder with both upper and lower motor neuron involvement. It presents with weakness, muscle wasting, spasticity involving the limbs, bulbar dysfunction, and, typically later in the disease, respiratory involvement. Up to 20% of patients may also have a frontotemporal-type dementia. Average duration of survival is 2 to 4 years from symptom onset, and the peak incidence is between the ages of 50 and 75 years. Only 10% of patients have familial forms, and the remainder have sporadic ALS.

scholarly journals Dissociation of disease onset, progression and sex differences from androgen receptor levels in a mouse model of amyotrophic lateral sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Doris Tomas ◽  
Victoria M. McLeod ◽  
Mathew D. F. Chiam ◽  
Nayomi Wanniarachchillage ◽  
Wah C. Boon ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Sex Differences ◽  
Androgen Receptor ◽  
Mouse Model ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Disease Onset ◽  
Disease Course ◽  
Male Mice ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder caused by loss of motor neurons. ALS incidence is skewed towards males with typically earlier age of onset and limb site of onset. The androgen receptor (AR) is the major mediator of androgen effects in the body and is present extensively throughout the central nervous system, including motor neurons. Mutations in the AR gene lead to selective lower motor neuron degeneration in male spinal bulbar muscular atrophy (SBMA) patients, emphasising the importance of AR in maintaining motor neuron health and survival. To evaluate a potential role of AR in onset and progression of ALS, we generated SOD1G93A mice with either neural AR deletion or global human AR overexpression. Using a Cre-LoxP conditional gene knockout strategy, we report that neural deletion of AR has minimal impact on the disease course in SOD1G93A male mice. This outcome was potentially confounded by the metabolically disrupted Nestin-Cre phenotype, which likely conferred the profound lifespan extension observed in the SOD1G93A double transgenic male mice. In addition, overexpression of human AR produced no benefit to disease onset and progression in SOD1G93A mice. In conclusion, the disease course of SOD1G93A mice is independent of AR expression levels, implicating other mechanisms involved in mediating the sex differences in ALS. Our findings using Nestin-Cre mice, which show an inherent metabolic phenotype, led us to hypothesise that targeting hypermetabolism associated with ALS may be a more potent modulator of disease, than AR in this mouse model.

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 Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Stefano Garofalo ◽  
Germana Cocozza ◽  
Alessandra Porzia ◽  
Maurizio Inghilleri ◽  
Marcello Raspa ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Mouse Model ◽  
Motor Neuron ◽  
Nk Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Nkg2d Ligands ◽  
Lateral Sclerosis

AbstractIn amyotrophic lateral sclerosis (ALS), immune cells and glia contribute to motor neuron (MN) degeneration. We report the presence of NK cells in post-mortem ALS motor cortex and spinal cord tissues, and the expression of NKG2D ligands on MNs. Using a mouse model of familial-ALS, hSOD1G93A, we demonstrate NK cell accumulation in the motor cortex and spinal cord, with an early CCL2-dependent peak. NK cell depletion reduces the pace of MN degeneration, delays motor impairment and increases survival. This is confirmed in another ALS mouse model, TDP43A315T. NK cells are neurotoxic to hSOD1G93A MNs which express NKG2D ligands, while IFNγ produced by NK cells instructs microglia toward an inflammatory phenotype, and impairs FOXP3+/Treg cell infiltration in the spinal cord of hSOD1G93A mice. Together, these data suggest a role of NK cells in determining the onset and progression of MN degeneration in ALS, and in modulating Treg recruitment and microglia phenotype.

Sign in / Sign up

Export Citation Format

Share Document