Neuronal TDP-43 regulates myelin formation via neurexin 1 mRNA stabilization
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE246657 | GEO | 2026/02/09
REPOSITORIES: GEO
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Project description:TAR DNA-binding protein 43 (TDP-43) is the major protein component of neuronal inclusions characterizing the adult-onset neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-TDP). Whereas TDP-43 was originally identified as a DNA-binding protein that bound the HIV-1 trans-activation response (TAR) DNA element, recent work elucidating its role in neurodegenerative disease pathogenesis has largely focused on TDP-43’s role as an RNA-binding protein. Here, we demonstrate that in human cells, TDP-43 binds DNA genome-wide, with strong enrichment at small nuclear RNA (snRNA) genes. Moreover, TDP-43 binding to snRNA genes is not dependent on RNA, and the snRNA products of TDP-43-bound sites are incorporated into Smith antigen-containing snRNPs. Furthermore, TDP-43 knockdown increases expression of bound snRNA genes, supporting a role for TDP-43 in the negative regulation of snRNA biogenesis. Finally, ALS-associated missense mutations in the gene encoding TDP-43, TARDBP, reduce binding to snRNA genes. Together, our data suggest that the DNA-binding role of TDP-43 is important in health and in disease, and aberrant TDP-43 binding to snRNA gene loci may alter splicing function in ALS and FTLD-TDP.
2023-12-21 | GSE117873 | GEO
Project description:The pathogenic mechanism by which dominant mutations in VCP cause multisystem proteinopathy (MSP), a rare neurodegenerative disease that presents as fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), remains unclear. To explore this, we inactivated VCP in murine postnatal forebrain neurons (VCP cKO). VCP cKO mice have cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction and TDP-43 inclusions resembling FTLD-TDP pathology. Conditional expression of a single disease-associated mutation, VCP-R155C, in a VCP null background similarly recapitulated features of VCP inactivation and FTLD-TDP, suggesting that this MSP mutation is hypomorphic. Comparison of transcriptomic and proteomic datasets from genetically defined patients with FTLD-TDP reveal that progranulin deficiency and VCP insufficiency result in similar profiles. These data identify a loss of VCP-dependent functions as a mediator of FTLD-TDP and reveal an unexpected biochemical similarity with progranulin deficiency.
2021-06-16 | GSE178257 | GEO
Project description:TDP-43 proteinopathies including frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic-acid binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed an endogenous model of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs its RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of aberrant acetylation-mimic TDP-43K145Q resulted in stress-induced phase-separated nuclear TDP-43 foci formation and loss-of-TDP-43-function in mouse primary neurons and human induced pluripotent stem cell (iPSC)-derived neurons. Aged mice harboring the single TDP-43K145Q mutation recapitulate several key hallmarks of neurodegenerative proteinopathies, including progressive TDP-43 phosphorylation and insolubility, cytoplasmic mis-localization, widespread transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which aberrant TDP-43 acetylation drives neuronal dysfunction and cognitive decline through alternative splicing and transcription of genes important in synaptic plasticity and apoptosis, providing a new paradigm to interrogate FTLD disease mechanisms and uncover disease-modifying therapeutics.
2023-01-09 | GSE216294 | GEO
Project description:Neurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system1. Human genetic studies established a causal role for protein assembly in neurodegeneration2. However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in electron cryo- microscopy (cryo-EM) have enabled the structures of the protein filaments to be determined from patient brains1. All diseases studied to date have been characterised by the self-assembly of proteins in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) Types A and B3,4. Here, we used cryo-EM to determine filament structures from the brains of individuals with FTLD-TDP Type C, one of the most common forms of sporadic FTLD- TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/284–N345 and ANXA11 residues L39– Y74 from their respective low-complexity domains (LCDs). Regions of TDP-43 and ANXA11 previously implicated in protein-protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as a ~22 kDa N-terminal fragment (NTF) lacking the annexin core domain. Immunohistochemistry of brain sections showed the co-localisation of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP Type C. This work establishes a central role for ANXA11 in FTLD-TDP Type C. The unprecedented formation of heteromeric amyloid filaments in human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.
2025-05-07 | PXD055345 | Pride
Project description:Dominant mutations in unrelated genes cause fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and include VCP, which is associated with multisystem proteinopathy (MSP). Conditional inactivation of VCP in postnatal forebrain neurons (VCP cKO) caused cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction, TDP-43 inclusions and hyperactivity. Quantitative proteomics and single nuclei RNA sequencing on VCP cKO brains identified synaptogenesis and the unfolded protein response as the most decreased and increased pathways respectively. Conditional expression of a single MSP disease mutation, VCP-R155C, in cortical neurons similarly recapitulated features of VCP inactivation and FTLD-TDP. Comparison of transcriptomic and proteomic datasets from genetically defined FTD patients revealed that profiles from GRN carriers were similar to VCP insufficiency. These data support a deficiency in VCP dependent functions as the pathogenic mechanism of FTLD-TDP and reveal an unexpected pathogenic similarity with progranulin deficiency. Enhancing VCP function may be therapeutic in MSP and related forms of FTLD-TDP.
2021-08-06 | PXD026685 | Pride
Project description:TAR DNA-binding protein 43 (TDP-43) is normally a nuclear RNA-binding protein that exhibits a range of functions including regulation of alternative splicing, RNA trafficking and RNA stability. However, in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), TDP-43 is abnormally phosphorylated, ubiquitinated, and cleaved, and is mislocalized to the cytoplasm where it forms distinctive aggregates. We previously developed a mouse model expressing human TDP-43 with a mutation in its nuclear localization signal (ΔNLS-hTDP-43) so that the protein preferentially localizes to the cytoplasm. These mice did not exhibit a significant number of cytoplasmic aggregates, but did display a loss of endogenous mouse nuclear TDP-43 as well as dramatic changes in gene expression as measured by microarray. Here, we analyze RNA-sequencing data from the ∆NLS-hTDP-43 mouse model, together with published RNA-sequencing data obtained previously from TDP-43 antisense oligonucleotide (ASO) knockdown mice and High Throughput Sequencing of RNA isolated by CrossLinking ImmunoPrecipitation (HITS-CLIP) data of TDP-43’s RNA binding targets to further investigate the dysregulation of gene expression in the ∆NLS model. This analysis reveals that the transcriptomic effects of the overexpression of the ΔNLS-hTDP-43 transgene are likely due to a gain of cytoplasmic function. Moreover, cytoplasmic TDP-43 expression alters transcripts that regulate chromatin assembly, the nucleolus, lysosomal function, and histone 3’ untranslated region (UTR) processing. These transcriptomic alterations correlate with observed histologic abnormalities in heterochromatin structure and nuclear size in transgenic mouse and human brains.
2015-10-15 | GSE65973 | GEO
Project description:Cytoplasmic aggregation TAR DNA binding protein 43 (TDP-43) is a hallmark pathology of motor neuron disease (MND), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). The disease-relevant protein-protein interactome of TDP-43 remains incompletely defined, elucidation of which will increase understanding of the molecular mechanisms responsible for disease. In this study, we aimed to identify true TDP-43 protein partners within the nucleus and cytoplasm and interactions at specific pathological stages of disease by correlating identified TDP-43 interaction partners in in human embryonic kidney HEK293, mouse neuroblastoma Neuro2A and mouse primary neurons. Using this approach combined with APEX2 proximity labelling and immunoprecipitation, and coupled with mass spectrometry analysis of protein interactors from nuclear and cytoplasmic fractions, we identified 58 putative wild-type TDP-43 interactors, including novel binding partners responsible for RNA metabolism and splicing. We verified the level of interaction of these protein partners in two other models: (1) a model presenting early pathological change showing TDP-43WT condensates in the nucleus through arsenite treatment and (2) a model stimulating another early-disease stage with TDP-43 containing ALS missense mutations (G294V and A315T) in the nucleus. We found that most interactors that presenting had a weaker affinity to mutant TDP-43 in the cytoplasm are involved in the translational machinery which could, over time, contribute to neurodegeneration. Understanding early pathological changes to TDP-43 in the nucleus and its specific interactions partners at different disease stages is critical to better understand ALS and FTLD mechanisms and provide potential therapeutic targets and novel biomarkers.
2025-05-14 | PXD054023 | Pride
Project description:Transactive response DNA-binding protein of 43 kDa (TDP-43), a heterogeneous nuclear ribonucleoprotein (hnRNP) with diverse activities, is a common denominator in several neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Orthologs of TDP-43 exist from mammals to invertebrates, but their functions in lower organisms remain poorly understood. Here we systematically studied mutant Caenorhabditis elegans lacking the nematode TDP-43 ortholog, TDP-1. To understand the global gene expression regulation induced by the loss of tdp-1, the C. elegans transcriptomes were compared between the N2 WT animals and the tdp-1(ok803lf) mutant. Transcriptional profiling demonstrated that the loss of TDP-1 altered expression of genes functioning in RNA processing and protein folding. These results suggest that the C. elegans TDP-1 as an RNA-processing protein may have a role in the regulation of protein homeostasis and aging. Global gene expression profiling was performed to compare the transcriptome of wild-type (N2) Caenorabditis elegans and that of tdp-1(ok803) loss-of-function mutant. We analyzed mixed stages of Caenorabditis elegans, wild-type N2 versus tdp-1(ok803), using the Affymetrix C. elegans genome array. Three biological replicates were performed.
2012-02-21 | E-GEOD-34113 | biostudies-arrayexpress
Project description:Understanding the mechanisms that drive TDP-43 pathology is integral to combating amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we generated a longitudinal quantitative proteomic map of the cortex from the cytoplasmic TDP-43 rNLS8 mouse model of ALS and FTLD and developed a complementary open-access webtool, TDP-map (https://shiny.rcc.uq.edu.au/TDP-map/). We identified distinct protein subsets enriched for diverse biological pathways with temporal alterations in protein abundance, including increases in protein folding factors prior to disease onset. This included increased levels of DnaJ homolog subfamily B member 5, DNAJB5, which also co-localized with TDP-43 pathology in diseased human motor cortex. DNAJB5 over-expression decreased TDP-43 aggregation in cell and cortical neuron cultures, and knockout of Dnajb5 exacerbated motor impairments caused by AAV-mediated cytoplasmic TDP-43 expression in mice. Together, these findings reveal molecular mechanisms at distinct stages of ALS and FTLD progression and suggest that protein folding factors could be protective in disease.
2024-01-31 | PXD042382 | Pride
Project description:Accumulation of abnormally phosphorylated TDP-43 (pTDP-43) is the main pathological finding characterizing affected neurons in most patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). At least four different subtypes of FTLD-TDP have been described, based on the morphology and neuroanatomical distribution of pathological TDP-43 accumulations. To understand the molecular basis of this heterogeneity that correlates with clinical presentations, we developed SarkoSpin, a new method for the biochemical isolation of pathological TDP-43 from complex tissues. Using postmortem samples of 79 patients and controls, we show that SarkoSpin allows the physical separation of pTDP-43 from ~99.8% of total proteins, including the extreme bulk of physiological TDP-43. Pathological TDP-43 extracted from different disease subtypes forms large and buoyant assemblies of distinct densities and 3-dimentional shapes that correlate with specific neuropathological classifications.
2018-10-10 | PXD007873 | Pride