Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA121697 | ENA |
REPOSITORIES: ENA
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Project description:Aims: Loss of nuclear TDP-43 characterises sporadic and most familial forms of amyotrophic lateral sclerosis (ALS). TDP-43 (encoded by TARDBP) has multiple roles in RNA processing. We aimed to determine whether 1) RNA splicing dysregulation is present in lower motor neurons in ALS and in a motor neuron-like cell model, and 2) TARDBP mutations (mtTARDBP) are associated with aberrant RNA splicing using patient-derived fibroblasts. Methods: Affymetrix exon arrays were used to study mRNA expression and splicing in lower motor neurons obtained by laser capture microdissection of autopsy tissue from individuals with sporadic ALS and TDP-43 proteinopathy. Findings were confirmed by qRT-PCR and in NSC34 motor neuronal cells following shRNA-mediated TDP-43 depletion. Exon arrays and immunohistochemistry were used to study mRNA splicing and TDP-43 expression in fibroblasts from patients with mtTARDBP-associated, sporadic and mutant SOD1-associated ALS. Results: We found altered expression of spliceosome components in motor neurons and widespread aberrations of mRNA splicing that specifically affected genes involved in ribonucleotide binding. This was confirmed in TDP-43 depleted NSC34 cells. Fibroblasts with mtTARDBP showed loss of nuclear TDP-43 protein and demonstrated similar changes in splicing and gene expression, that were not present in fibroblasts from patients with sporadic or SOD1-related ALS. Conclusion: Loss of nuclear TDP-43 is associated with RNA processing abnormalities in ALS motor neurons, patient-derived cells with mtTARDBP, and following artificial TDP-43 depletion, suggesting that splicing dysregulation directly contributes to disease pathogenesis. Key functional pathways affected include those central to RNA metabolism. RNA was extracted from lower motor neurons obtained by laser capture microdissection from autopsy material from neurologically healthy controls (n=6) and cases of sporadic ALS (n=3) and ALS due to C9ORF72 mutations (n=3).
2014-06-01 | E-GEOD-56500 | biostudies-arrayexpress
Project description:Aims: Loss of nuclear TDP-43 characterises sporadic and most familial forms of amyotrophic lateral sclerosis (ALS). TDP-43 (encoded by TARDBP) has multiple roles in RNA processing. We aimed to determine whether 1) RNA splicing dysregulation is present in lower motor neurons in ALS and in a motor neuron-like cell model, and 2) TARDBP mutations (mtTARDBP) are associated with aberrant RNA splicing using patient-derived fibroblasts. Methods: Affymetrix exon arrays were used to study mRNA expression and splicing in lower motor neurons obtained by laser capture microdissection of autopsy tissue from individuals with sporadic ALS and TDP-43 proteinopathy. Findings were confirmed by qRT-PCR and in NSC34 motor neuronal cells following shRNA-mediated TDP-43 depletion. Exon arrays and immunohistochemistry were used to study mRNA splicing and TDP-43 expression in fibroblasts from patients with mtTARDBP-associated, sporadic and mutant SOD1-associated ALS. Results: We found altered expression of spliceosome components in motor neurons and widespread aberrations of mRNA splicing that specifically affected genes involved in ribonucleotide binding. This was confirmed in TDP-43 depleted NSC34 cells. Fibroblasts with mtTARDBP showed loss of nuclear TDP-43 protein and demonstrated similar changes in splicing and gene expression, that were not present in fibroblasts from patients with sporadic or SOD1-related ALS. Conclusion: Loss of nuclear TDP-43 is associated with RNA processing abnormalities in ALS motor neurons, patient-derived cells with mtTARDBP, and following artificial TDP-43 depletion, suggesting that splicing dysregulation directly contributes to disease pathogenesis. Key functional pathways affected include those central to RNA metabolism. RNA was extracted from fibroblasts grown from neurologically healthy controls (n=6) and 3 groups of patients with ALS: 1) sporadic cases (n=6); 2) cases due to mutations of SOD1 (n=4); 3) cases due to mutations of TARDBP (n=3). The three ALS groups were compared to the controls.
2014-06-01 | E-GEOD-33855 | biostudies-arrayexpress
Project description:Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons. Approximately 10% of ALS cases have a known family history of the disease and mutations in multiple genes have been identified. ALS-linked mutations in CCNF were recently reported, however the pathogenic mechanisms associated with these mutations are yet to be established. To investigate possible mechanisms, an in vitro model of ALS was developed that expressed mutant CCNF in a neuronal cell line (Neuro-2a). Proteomic analysis of this in vitro model identified the disruption of several cellular pathways, including those associated with caspase-3 mediated cell death and axonal outgrowth. To establish whether these findings were replicated in vivo, a zebrafish model was developed. Transient overexpression of human mutant CCNF in zebrafish led to increased caspase-3 activity, increased cell death and a motor neuron axonopathy consisting of shortened primary motor axons and increased frequency of aberrant axonal branching. A significant correlation between the severity of this mutant CCNF-induced axonopathy and reduced motor function was also demonstrated in this model, with zebrafish expressing the mutant protein demonstrating an impaired motor response to a light stimulus. This is the first report of an ALS-linked CCNF mutation in vivo and indicates that zebrafish will be a useful tool to model the pathogenesis of CCNF-linked motor neuron degeneration.
2017-05-22 | PXD005131 | Pride
Project description:Amyotrophic lateral sclerosis and primary lateral sclerosis are two syndromic variants within the motor neurone disease spectrum. Whilst primary lateral sclerosis is associated with loss of upper motor neurons and a more benign disease course up to 17yrs, amyotrophic lateral sclerosis is caused by loss of both upper and lower motor neurons and has an average disease course of 2-3 years. The majority of cases are sporadic, thereby limiting the availability of cellular models for investigating pathogenic disease mechanisms. The aim of the present study was to evaluate fibroblasts as a cellular model for sporadic amyotrophic lateral sclerosis and primary lateral sclerosis, to establish whether disease-related dysregulated biological processes recapitulate those seen in the central nervous system and to elucidate pathways that distinguish between the two disease phenotypes. We used microarray analysis to determine the differences in gene expression between fibroblasts derived from skin biopsies taken from sporadic amyotrophic lateral sclerosis and primary lateral sclerosis neurologically normal human controls
2014-04-16 | E-GEOD-56808 | biostudies-arrayexpress
Project description:Amyotrophic lateral sclerosis (ALS) is categorized into 10% familial and 90% sporadic cases. While the space of 10% familial ALS is crowded with mutations in many genes of diverse functions, most ALS-associated mutations could not faithfully recapitulate the disease phenotype in animal models. Remarkably, nearly half of sporadic ALS patients exhibit defective mitochondrial respiratory complex Ⅳ (CⅣ). To establish the causal role of defective CⅣ in inducing ALS, we employed TALE-based mtDNA editing to mimic ALS-linked mutations in CⅣ compared to other respiratory complexes in rat neurons and demonstrated that mutations exclusively introduced to mtDNA-encoded CⅣ subunits are sufficient to cause a full spectrum of ALS-like phenotypes, including selective motor neuron loss, SOD1 overexpression and cytosolic TDP-43 aggregation. These findings reveal a broad basis for sporadic ALS, provide critical insights into the selective motor neuron vulnerability, and present a faithful animal model for advancing ALS therapy.
2024-12-18 | GSE252875 | GEO
Project description:Amyotrophic lateral sclerosis (ALS) is categorized into 10% familial and 90% sporadic cases. While the space of 10% familial ALS is crowded with mutations in many genes of diverse functions, most ALS-associated mutations could not faithfully recapitulate the disease phenotype in animal models. Remarkably, nearly half of sporadic ALS patients exhibit defective mitochondrial respiratory complex Ⅳ (CⅣ). To establish the causal role of defective CⅣ in inducing ALS, we employed TALE-based mtDNA editing to mimic ALS-linked mutations in CⅣ compared to other respiratory complexes in rat neurons and demonstrated that mutations exclusively introduced to mtDNA-encoded CⅣ subunits are sufficient to cause a full spectrum of ALS-like phenotypes, including selective motor neuron loss, SOD1 overexpression and cytosolic TDP-43 aggregation. These findings reveal a broad basis for sporadic ALS, provide critical insights into the selective motor neuron vulnerability, and present a faithful animal model for advancing ALS therapy.
2024-12-18 | GSE275999 | GEO
Project description:Aims: Loss of nuclear TDP-43 characterises sporadic and most familial forms of amyotrophic lateral sclerosis (ALS). TDP-43 (encoded by TARDBP) has multiple roles in RNA processing. We aimed to determine whether 1) RNA splicing dysregulation is present in lower motor neurons in ALS and in a motor neuron-like cell model, and 2) TARDBP mutations (mtTARDBP) are associated with aberrant RNA splicing using patient-derived fibroblasts. Methods: Affymetrix exon arrays were used to study mRNA expression and splicing in lower motor neurons obtained by laser capture microdissection of autopsy tissue from individuals with sporadic ALS and TDP-43 proteinopathy. Findings were confirmed by qRT-PCR and in NSC34 motor neuronal cells following shRNA-mediated TDP-43 depletion. Exon arrays and immunohistochemistry were used to study mRNA splicing and TDP-43 expression in fibroblasts from patients with mtTARDBP-associated, sporadic and mutant SOD1-associated ALS. Results: We found altered expression of spliceosome components in motor neurons and widespread aberrations of mRNA splicing that specifically affected genes involved in ribonucleotide binding. This was confirmed in TDP-43 depleted NSC34 cells. Fibroblasts with mtTARDBP showed loss of nuclear TDP-43 protein and demonstrated similar changes in splicing and gene expression, that were not present in fibroblasts from patients with sporadic or SOD1-related ALS. Conclusion: Loss of nuclear TDP-43 is associated with RNA processing abnormalities in ALS motor neurons, patient-derived cells with mtTARDBP, and following artificial TDP-43 depletion, suggesting that splicing dysregulation directly contributes to disease pathogenesis. Key functional pathways affected include those central to RNA metabolism. RNA was extracted from NSC34 motor neuronal cells depleted of TDP-43 by shRNA (n=4), treated with control shGFP (n=4), and treated with control shLuciferase (n=3).
2014-06-01 | E-GEOD-56503 | biostudies-arrayexpress
Project description:Mutations in the RNA binding protein, Fused in Sarcoma (FUS), lead to amyotrophic lateral sclerosis (ALS), the most frequent form of motor neuron disease. Cytoplasmic aggregation and defective DNA repair machinery are etiologically linked to mutant FUS-associated ALS. Although FUS is involved in numerous aspects of RNA processing, little is understood about the pathophysiological mechanisms of mutant FUS. Here, we employed RNA-sequencing technology in Drosophila brains expressing FUS to identify significantly altered genes and pathways involved in FUS-mediated neurodegeneration.
2021-05-05 | GSE173838 | GEO
Project description:To identify molecular differences between closely related motor neurons relevant for understanding of neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), we exploited induced cranial and spinal motor neuron populations from mouse embryonic stem cells. We performed a large scale time-dependent TMT-based proteomics analysis in the presence and absence of protein misfolding stress. We profiled ~8,600 proteins from two different motor neuron cell lines, measured in two replicates and three time points.
2024-03-06 | PXD018070 | Pride
Project description:Amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease, is characterized by progressive muscle weakness and paralysis caused by degeneration of upper and lower motor neurons. A major breakthrough in understanding the genetics of ALS was the discovery of a GGGGCC hexanucleotide repeat expansion (HRE) within the non-coding region of chromosome 9 open reading frame 72 (C9orf72) as the most common mutation in both familial and sporadic forms of ALS [25, 80]. We report that C9orf72 loss of function and poly(GP) expression act together to induce motor neuron degeneration and paralysis. These synergistic properties of C9orf72 mutation affect autophagy, thus resulting in poly(GP) and p62 aggregation. In this context, poly(GP) accumulation occurs in motor neurons preferentially, along with swollen mitochondria, a typical signature of mitophagy defects. In motor neurons, accumulated abnormal mitochondria engage caspase cascade, ultimately giving rise to apoptotic cell death of motor neurons that results in paralysis
2021-05-11 | PXD023967 | Pride