Targeting low levels of MIF expression as a potential therapeutic strategy for ALS
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE246397 | GEO | 2024/01/11
REPOSITORIES: GEO
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Project description:We established iPSCs from healthy donors, SOD1-ALS and TDP43-ALS patients. Using our differentiation protocol originally developed by Reinhardt et al.,2013, we diferentiated these iPSCs toward spinal motor neurons (MNs) and reproduce ALS pathology in a dish. To extend our understanding of finding different molecular mechanisms and pathways related to SOD1- and TDP43 mutations in ALS disease, we have performed a comprehensive gene expression profiling study using RNA-Seq of the iPSC-derived MN models from control individuals and carefully compared with those from SOD1-ALS and TDP43-ALS patients. To generate novel hypotheses of putative underlying molecular mechanisms in ALS, we used human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs) from SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls to perform high-throughput RNA-sequencing (RNA-Seq). An integrated bioinformatics approach was employed to identify differentially expressed genes (DEGs) and key pathways underlying these familial forms of the disease (fALS). In TDP43-ALS, we found dysregulation of transcripts encoding components of the transcriptional machinery and transcripts involved in splicing regulation were particularly affected. In contrast, less is known about the role of SOD1 in RNA metabolism in motor neurons. Here we found that many transcripts relevant for mitochondrial function were specifically altered in SOD1-ALS, indicating transcriptional signatures and expression patterns can vary significantly depending on the causal gene that is mutated. Surprisingly, however, we identified a clear downregulation of genes involved in protein translation in SOD1-ALS suggesting that ALS-causing SOD1 mutations shift cellular RNA abundance profiles to cause neural dysfunction. Altogether, we provided here an extensive profiling of mRNA expression in two ALS models at the cellular level, corroborating the major role of RNA metabolism and protein translation as a common pathomechanism in ALS
2022-08-17 | GSE210969 | GEO
Project description:Gene expression profiling has been performed previously on motor cortex and spinal cord homogenates and of sporadic ALS cases and controls, to identify genes and pathways differentially expressed in ALS. More recent studies have combined the use of laser capture microdissection (LCM) with gene expression profiling to isolate the motor neurons from the surrounding cells, such as microglia and astrocytes, in order to determine those genes differentially expressed in the vulnerable cell population – i.e. motor neuron. The aim of the present study is to combine LCM and microarray analysis to determine those genes and pathways differentially expressed in MNs from human SOD1-related MND and to establish potential pathways for therapeutic intervention. Keywords: Human motor neurons The aim of this study was to determine the gene expression profiles from a small subset of cases which all carry mutations in the SOD1 gene. Expression profiles from isolated motor neurons in SOD1-related ALS cases were compared to those from control motor neurons, in order to establish the pathways implicated in SOD1-related motor neuronal cell death. The 'control' samples were originally submitted to GEO as GSE19332.
2011-01-01 | E-GEOD-20589 | biostudies-arrayexpress
Project description:Misfolded soluble trimeric species of superoxide dismutase 1 (SOD1) are associated with increased death in neuron-like cell models and greater disease severity in amyotrophic lateral sclerosis (ALS) patients compared to insoluble protein aggregates. The mechanism by which structurally independent SOD1 trimers cause cellular toxicity is unknown but may be a driver of disease pathology. Here, we uncovered the SOD1 trimer transcriptome. We identified key pathways using transcriptomic data from motor neuron-like cells (NSC-34s) expressing SOD1 trimers. We discovered differential gene expression in cells that express SOD1 trimers with selective enrichment of genes responsible for protein localization to membranes and a global upregulation of cellular senescence pathways. Our investigation highlights key protein factors and pathways within each system, revealing a plausible intersection of genetic and pathophysiological mechanisms in ALS through interactions involving SOD1 trimers.
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Project description:We established iPSCs from healthy donors, FUS-ALS and SOD1-ALS patients. Using our differentiation protocol originally developed by Reinhardt et al.,2013, we diferentiated these iPSCs toward spinal motor neurons (MNs) and reproduce ALS pathology in a dish. To extend our understanding of finding different molecular mechanisms and pathways related to FUS- and SOD mutations in ALS disease, we have performed a comprehensive gene expression profiling study using microarray hybridization of the iPSC-derived MN models from control individuals and carefully compared with those from FUS-ALS and SOD1-ALS patients. In addition, we further analyzed previously published independent datasets containing the genome-wide RNA profiling of iPSC-derived MN samples from patients with FUS and SOD1 mutations and controls. This microaray dataset GSE10638 (Fujimori et al., 2018) was retrieved from GEO database and was screened to identifiy potential drug candidates which suppressed the detected ALS-related phenotypes of these ALS models. Finally, we made a systematic comparison with our results to the ones independently obtained previously.Here through this study, we create a gene profile of ALS by analyzing the differentially expressed genes (DEGs), the kyoto encyclopedia of Genes and Genomes (KEGG) pathways, the interactome as well as transcription factor profiles (TF) that would identify altered functional/molecular signatures and their interactions at both transcriptional (mRNAs) and translational levels (hub proteins and TFs) which stands validation across the different datasets (including different differentiation protocols etc.). By doing so we provide condensed pathophysiological pathways of FUS-ALS and SOD1-ALSto better understand the biological mechanisms underlying motor neuron disease.
2020-09-21 | GSE158264 | GEO
Project description:Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the selective loss of motor neurons. Mutations in Cu/Zn superoxide dismutase (SOD1) are the second most common cause of ALS and it is now well accepted that they result in a gain of toxicity due to protein misfolding. We previously demonstrated in the SOD1G93A rat model that misfolded SOD1 exists as distinct conformers and deposits on mitochondrial subpopulations. Here, using SOD1G93A rats coupled with conformation-restricted antibodies for misfolded SOD1 (AMF7-63 and B8H10), we identified the interactomes of the mitochondrial pools of misfolded SOD1. This strategy identified binding partners that uniquely interacted with either AMF7-63- or B8H10-reactive SOD1 conformers as well as a high proportion of interactors common to both conformers. Of this latter set, we identified the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6) and determined that exposure of the SOD1 functional loops facilitates this interaction. However, this conformational criterion is not universally fulfilled by all SOD1 mutants and differentiates TRAF6-interacting from non-interacting SOD1 mutants. Functionally, TRAF6 stimulates mutant SOD1 polyubiquitination and aggregation. While TRAF6 E3 ubiquitin ligase activity is required for the former, it is dispensable for the latter, indicating that the polyubiquitination and aggregation of mutant SOD1 mediated by TRAF6 are independent events. We propose that misfolded SOD1 binding to TRAF6 may be relevant to ALS disease.
2020-02-24 | PXD015279 | Pride
Project description:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons (MNs). It was shown that human astrocytes with mutations in genes associated with ALS, like C9orf72 (C9) or SOD1, reduce survival of MNs. Astrocyte toxicity may be related to their dysfunction or the release of neurotoxic factors. We used human induced pluripotent stem cell-derived astrocytes from ALS patients carrying C9orf72 mutations and non-affected donors. We utilized these cells to investigate astrocytic induced neuronal toxicity, changes in astrocyte transcription profile as well as changes in secretome profiles. We report that C9-mutated astrocytes are toxic to MNs via soluble factors. The toxic effects of astrocytes are positively correlated with the length of astrocyte propagation in culture, consistent with the age-related nature of ALS. We show that C9-mutated astrocytes downregulate the secretion of several antioxidant proteins. In line with these findings, we show increased astrocytic oxidative stress and senescence. Importantly, media conditioned by C9-astrocytes increased oxidative stress in wild type MNs. Our results suggest that dysfunction of C9-astrocytes leads to oxidative stress of themselves and MNs, which probably contributes to neurodegeneration. Our findings suggest that therapeutic strategies in familial ALS must not only target MNs but also focus on astrocytes to abrogate nervous system injury.
2020-06-01 | GSE142730 | GEO
Project description:Recent genetic studies of ALS patients have identified several forms of ALS that are associated with mutations in RNA binding proteins. In animals or cultured cells, such defects broadly affect RNA metabolism. This raises the question of whether all forms of ALS have general effects on RNA metabolism. We tested this hypothesis in a mouse model of ALS that is transgenic for a human disease-causing mutation in the enzyme superoxide dismutase 1 (SOD1). We analyzed RNA from laser-captured spinal cord motor neuron cell bodies of the mutant SOD1 strain, comparing the RNA profile with that from a corresponding wild-type SOD1 transgenic strain. We prepared the samples from animals that were presymptomatic, but which manifested abnormalities at the cellular level that are seen in ALS, including aggregation of the mutant protein in motor neuron cell bodies and defective morphology of neuromuscular junctions, the connections between neuron and muscle. We observed only minor changes in the level and splicing of RNA in the SOD1 mutant animals as compared with wild-type, suggesting that mutant SOD1 produces the toxic effects of ALS by a mechanism that does not involve global RNA disturbance. RNA-Seq of laser microdissection of motor neuron bodies from two biological replicates each of SOD1 YFP (wildtype 592) and SOD1 G85R YFP (737) transgenic mice.
2012-12-04 | E-GEOD-38820 | biostudies-arrayexpress
Project description:Mutations causing amyotrophic lateral sclerosis (ALS) strongly implicate regulators of RNA-processing that are ubiquitously expressed throughout development. To understand the molecular impact of ALS-causing mutations on early neuronal development and disease, we performed transcriptomic analysis of differentiated human control and VCP-mutant induced pluripotent stem cells (iPSCs) during motor neurogenesis. We identify intron retention (IR) as the predominant splicing change affecting early stages of wild-type neural differentiation, targeting key genes involved in the splicing machinery. Importantly, IR occurs prematurely in VCP-mutant cultures compared with control counterparts; these events are also observed in independent RNAseq datasets from SOD1- and FUS-mutant motor neurons (MNs). Together with related effects on 3’UTR length variation, these findings implicate alternative RNA-processing in regulating distinct stages of lineage restriction from iPSCs to MNs, and reveal a temporal deregulation of such processing by ALS mutations. Thus, ALS-causing mutations perturb the same post-transcriptional mechanisms that underlie human motor neurogenesis.
2018-03-08 | GSE98289 | GEO
Project description:Neurofilament (NF) accumulation is a pathological hallmark observed in motor neurons (MNs) of patients with Amyotrophic Lateral Sclerosis (ALS) and levels of NF in fluids is becoming the prime biomarker of ALS progression. However, the underlying mechanisms linking NF accumulations and MN degeneration are not elucidated. Here, we show that integrity of the axonal initial segment (AIS), the region of action potential initiation and of polarized trafficking, is impaired by NF accumulations in human MNs carrying mutations in the two main causal ALS genes: C9ORF72 and SOD1. We show that in mutant MNs derived from induced pluripotent stem cells, both light (NF-L) and phosphorylated heavy chains (pNF-H) accumulated progressively with MN aging and that pNF-H accumulation in the AIS region led to significant structural and molecular alterations. In parallel, ALS MNs acquired altered excitability with aging. Focusing on axonal organization appears as an effective readout for MN cell death and preserving AIS integrity could have important therapeutic implications.
2024-07-03 | GSE200474 | GEO
Project description:The transgenic mice expressing the human mutated form (G93A) of the SOD1 gene represent a valuable model of Amyotrophic Lateral Sclerosis (ALS). SOD1 is one of the main causative genes of familial ALS which accounts for 10% of cases. These transgenic animals develop a motorneuronal pathology that recapitulates well the neuropathological features occuring in ALS patients, and the progression of the disease can be monitored by a series of motor tests. Gastrocnemius is the first and most affected muscle in the disease, while triceps is relatively spared. Gene expression data of degenerating motor neurons at different disease stages are already available, while gene expression data on the muscle tissue are missing. Our aim is to define the role of muscle in motor neuron degeneration in ALS. Keywords: Single stage analysis (presymptomatic stage, 7 week-old mice) We considered two sets of muscle at presymptomatic stage (7 weeks): gastrocnemius and triceps from 4 transgenic SOD1G93A and 4 non-transgenic mice (NTg).
2010-03-04 | E-GEOD-16360 | biostudies-arrayexpress