TTA/TDP Mice Expression Array
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE25182 | GEO | 2010/11/10
SECONDARY ACCESSION(S): PRJNA134527
REPOSITORIES: GEO
Similar Datasets
Project description:Transgenic (Tg) mice expressing nuclear or cytoplasmic human TDP-43 were generated. Tg mice had motor spasticity and forebrain neurodegeneration. Human TDP-43 reduced mouse TDP-43 in nuclei of affected neurons. Tg mice showed alterations in transcripts related to chromatin assembly. Cerebral cortex from 21 transgenic mice and controls were assayed after two weeks off doxycyline diet as described in Igaz et al.
2010-11-10 | E-GEOD-25182 | biostudies-arrayexpress
Project description:We report the enrichment of mRNAs with motor neuron specific TDP-43 and tagged ribosomes in control as well as multiple models of TDP-43 induced neurodegeneration. Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative disease in which 97% of patients exhibit cytoplasmic aggregates containing the RNA binding protein TDP-43. The goal of this study is to understand the translational consequences of TDP-43 pathology. Using the GAL4-UAS system, we expressed TDP-43WT and TDP-43G298S in the motor neurons of our drosophila to induce ALS-like neurodegeneration. TDP-43 was immunoprecipitated from the larvae at the 3rd instar stage; TDP-43 associated mRNAs, the whole larvae input, and ventral nerve cords of the same genotype were then sequenced. To identify translational changes we conducted TRAP (translating ribosome affinity purifications) in 3rd instar larvae by immunoprecipitating the motor neuron specific tagged ribosomal subunit RpL10-GFP in both ALS models as well as a RpL10-GFP control. The RpL10-GFP associated mRNAs, the whole larval input, and ventral nerve cords of the same genotype. From this data, we identified both compensatory alterations to translation induced by TDP-43 pathology and direct targets of TDP-43 mediated translational inhibition.
2021-03-31 | GSE156222 | GEO
Project description:TDP-43, a DNA/RNA binding protein involved in RNA transcription and splicing has been associated with the pathophysiology of neurodegenerative diseases, including ALS. However, the function of TDP-43 in motor neurons remains undefined. Here, we employ both gain- and loss-of-function approaches to determine roles of TDP-43 in motor neurons. Mice expressing human TDP-43 in neurons exhibited growth retardation and premature death that are characterized by abnormal intranuclear inclusions comprised of TDP-43 and Fused in Sarcoma (FUS), and massive accumulation of mitochondria in TDP-43-negative cytoplasmic inclusions in motor neurons, lack of mitochondria in motor axon terminals and immature neuromuscular junctions. Whereas elevated level of TDP-43 disrupts the normal nuclear distribution of Survival Motor Neuron (SMN)-associated Gemini of coiled bodies (GEMs) in motor neurons, its absence prevents the formation of GEMs in the nuclei of these cells. Moreover, transcriptome-wide deep sequencing analysis revealed that decrease in abundance of neurofilament transcripts contributed to the reduction of caliber of motor axons in TDP-43 mice. In concert, our findings indicate that TDP-43 participates in pathways critical for motor neuron physiology, including those that regulate the normal distributions of SMN-associated GEMs in the nucleus and mitochondria in the cytoplasm. Human TDP-43 coding region were inserted into pThy1.2 expression cassette and subsequently injected into C57BL/6;SJL hybrid mouse embryos to make human TDP-43 transgenic mice
2010-07-30 | E-GEOD-22351 | biostudies-arrayexpress
Project description:Triggering receptor expressed on myeloid cell 2 (TREM2) is linked to neurodegenerative disease risk. However, the function of TREM in neurodegeneration is still unclear. Here we investigated the role of microglial TREM2 in TAR-DNA binding protein 43 kDa (TDP-43)-related neurodegeneration using viral-mediated and transgenic mouse models. We found that TREM2 deficiency impaired phagocytic clearance of pathological TDP-43 by microglia, and enhanced neuronal damage and motor impairments. Mass cytometry analysis revealed that hTDP-43 induced a TREM2-dependent subpopulation of microglia with high CD11c expression and phagocytic ability. Using mass spectrometry and surface plasmon resonance analysis, we further demonstrated an interaction between TDP-43 and TREM2 in vitro and in vivo as well as in ALS patient tissues. We computationally identified the region within hTDP-43 that interacts with TREM2. Our data highlights that TDP-43 is a possible ligand for microglial TREM2 and that this interaction mediates neuroprotection effects of microglia in TDP-43-related neurodegeneration.
2022-08-12 | PXD029429 | Pride
Project description:TDP-43, a DNA/RNA binding protein involved in RNA transcription and splicing has been associated with the pathophysiology of neurodegenerative diseases, including ALS. However, the function of TDP-43 in motor neurons remains undefined. Here, we employ both gain- and loss-of-function approaches to determine roles of TDP-43 in motor neurons. Mice expressing human TDP-43 in neurons exhibited growth retardation and premature death that are characterized by abnormal intranuclear inclusions comprised of TDP-43 and Fused in Sarcoma (FUS), and massive accumulation of mitochondria in TDP-43-negative cytoplasmic inclusions in motor neurons, lack of mitochondria in motor axon terminals and immature neuromuscular junctions. Whereas elevated level of TDP-43 disrupts the normal nuclear distribution of Survival Motor Neuron (SMN)-associated Gemini of coiled bodies (GEMs) in motor neurons, its absence prevents the formation of GEMs in the nuclei of these cells. Moreover, transcriptome-wide deep sequencing analysis revealed that decrease in abundance of neurofilament transcripts contributed to the reduction of caliber of motor axons in TDP-43 mice. In concert, our findings indicate that TDP-43 participates in pathways critical for motor neuron physiology, including those that regulate the normal distributions of SMN-associated GEMs in the nucleus and mitochondria in the cytoplasm.
2010-07-31 | GSE22351 | GEO
Project description:We identify the RNA targets of TAR DNA-binding protein 43 (TDP-43) from cortical neurons by RNA immunoprecipitation followed by deep sequencing (RIP-seq). We identify 4352 highly enriched RNA targets of TDP-43. We determined that the canonical TDP-43 binding site (TG)n was 55.1-fold enriched in our TDP-43 library. Moreover, our analysis shows there is often an adenine in the middle of the motif, (TG)nTA(TG)m. TDP-43 RNA targets are particularly enriched for Gene Ontology terms related to RNA metabolism, neuronal development, and synaptic function.
2010-11-04 | GSE25032 | GEO
Project description:We identify the RNA targets of TAR DNA-binding protein 43 (TDP-43) from cortical neurons by RNA immunoprecipitation followed by deep sequencing (RIP-seq). We identify 4352 highly enriched RNA targets of TDP-43. We determined that the canonical TDP-43 binding site (TG)n was 55.1-fold enriched in our TDP-43 library. Moreover, our analysis shows there is often an adenine in the middle of the motif, (TG)nTA(TG)m. TDP-43 RNA targets are particularly enriched for Gene Ontology terms related to RNA metabolism, neuronal development, and synaptic function. Examination of TDP-43 RNA targets in rat cortical neurons by RIP-seq. Chantelle F. Sephton isolated the TDP-43:RNA complexes and generated the cDNA library for deep sequencing. Email: chantelle.sephton@utsouthwestern.edu Phone: 214-648-4119 Fax: 214-648-1801 ULR: http://www8.utsouthwestern.edu/utsw/cda/dept120915/files/151135.html Organization name: University of Texas Southwestern Medical Center at Dallas Department: Neuroscience Lab: Gang Yu lab Street: 6000 Harry Hines Blvd. City: Dallas State: Texas ZIP: 75390 Country: USA
2010-11-04 | E-GEOD-25032 | biostudies-arrayexpress
Project description:The majority of patients with amyotrophic lateral sclerosis (ALS) have abnormal TDP-43 aggregates in the nucleus and/or cytosol of their surviving neurons and glia. Although accumulating evidence indicates that astroglial dysfunctions contribute to motor neuron degeneration in ALS, the normal physiological functions of TDP-43 in astrocytes are largely unknown and whether the loss of astroglial TDP-43 contributes to ALS remains to be clarified. Here, we showed that TDP-43 deleted astrocytes showed cell-autonomously enhanced GFAP immunoreactivity without affecting astrocyte or microglia proliferation. At the transcriptomic level, TDP-43 deleted astrocytes resemble the A1-reactive astrocytes and induce microglia to increase C1q expression. These astrocytic changes do not cause the loss of motor neurons in spinal cords or denervation at the neuromuscular junctions. In contrast, there was a selective reduction of mature oligodendrocytes, but not oligodendrocyte precursor cells, suggesting a tri-glial dysfunction mediated by TDP-43-deleted astrocytes. Mice with astroglial TDP-43 deletion developed motor, but not sensory, deficits. Taken together, our results demonstrate that TDP-43 is required to maintain the protective functions of astrocytes relevant to the development of motor deficits in mice.
2020-11-01 | GSE156542 | GEO
Project description:MicroRNAs (miRNAs) play important roles in a wide range of cellular processes. Aberrant regulation of miRNA genes contributes to human diseases, including cancer. The TAR DNA binding protein 43 (TDP-43), a DNA/RNA binding protein associated with neurodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs whose expression levels are regulated by TDP-43 using RNA-Seq coupled with siRNA-mediated knockdown approach. TDP-43 knocking down affected the expression of a number of miRNAs. Alterations in isomiR patterns and miRNA arm selection after TDP-43 knockdown suggest a role of TDP-43 in miRNA editing. We examined correlation of selected TDP-43 associated miRNAs and their candidate target genes in human cancers. Our data reveal highly complex roles of TDP-43 in regulating different miRNAs and their target genes. Our results suggest that TDP-43 may promote migration of lung cancer cells by regulating miR-423-3p expression. On the other hand, TDP-43 increases miR-500a-3p expression and binds to the mature miR-500a-3p sequence. Low expression of miR-500a-3p was associated with poor survival of lung cancer patients, suggesting that TDP-43 may have a suppressive role in cancer by regulating miR-500a-3p. Our experiments reveal that cancer-associated genes LIF and PAPPA may be targets of miR-500a-3p. Together with other studies, our work suggests that TDP-43-regulated miRNAs may play multi-facet roles in the pathogenesis of cancer. small RNA seq in SH-SY-5Y, SNB-19 and HT22 (TDP-43 siRNA VS Control siRNA)
2016-08-02 | E-GEOD-85065 | biostudies-arrayexpress
Project description:Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with loss of nuclear TDP-43. Here we identify that TDP-43 regulates expression of the neuronal growth-associated factor stathmin-2. Lowered TDP-43 levels, which reduce its binding to sites within the first intron of stathmin-2 pre-mRNA, uncover a cryptic polyadenylation site whose utilization produces a truncated, non-functional mRNA. Reduced stathmin-2 expression is found in neurons trans-differentiated from patient fibroblasts expressing an ALS-causing TDP-43 mutation, in motor cortex and spinal motor neurons from sporadic ALS patients and familial ALS patients with expansion in C9orf72, and in induced pluripotent stem cell (iPSC)-derived motor neurons depleted of TDP-43. Remarkably, while reduction in TDP-43 is shown to inhibit axonal regeneration of iPSC-derived motor neurons, rescue of stathmin-2 expression restores axonal regenerative capacity. Thus, premature polyadenylation-mediated reduction in stathmin-2 is a hallmark of ALS/FTD that functionally links reduced nuclear TDP-43 function to enhanced neuronal vulnerability.
2019-01-01 | GSE122069 | GEO