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Effects of TDP-43 overexpression on neuron proteome and morphology in vitro

ABSTRACT: Primary neuronal cultures were prepared from transgenic mice overexpressing wildtype human TDP-43 under the control of the prion promoter (hTDP-43Prp).

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Neuron

SUBMITTER: Richard Wilson

LAB HEAD: Dr Richard Wilson

PROVIDER: PXD022671 | Pride | 2026-06-29

REPOSITORIES: Pride

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			Action	DRS
	1708_RA_Het_1.raw	Raw
	1708_RA_Het_2.raw	Raw
	1708_RA_Het_3.raw	Raw
	1708_RA_Hom_1.raw	Raw
	1708_RA_Hom_2.raw	Raw

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Publications

Effects of TDP-43 overexpression on neuron proteome and morphology in vitro.

Atkinson Rachel A K RAK Fair Hannah L HL Wilson Richard R Vickers James C JC King Anna E AE

Molecular and cellular neurosciences 20210518

TDP-43 is pathologically and genetically with associated amyotrophic lateral sclerosis and frontotemporal lobar degeneration. These diseases are characterized by significant neurite defects, including cytoskeletal pathology. The involvement of TDP-43 in the degeneration of neurons in these diseases are not yet well understood, however accumulating evidence shows involvement in neurite outgrowth, remodelling and in regulation of many components of the neuronal cytoskeleton. In order to investigat ...[more]

PMID: 34015498

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Effect of TDP-43 overexpression on neuron structure, function and proteome in vitro

Project description:Discovery of proteins and pathways affected by overexpression of the protein TDP-43 in neurons cultured from wild-type and mice homogygous for the transgene.

2023-04-27 | PXD014889 | Pride

Identifying modifiers of seed-induced TDP-43 loss of function

Project description:Both gain of toxicity and loss of normal function of the RNA-binding protein TDP-43 contribute to neurodegeneration in ALS and FTD, but their mechanistic connection remains unclear. Increasing evidence suggests that TDP-43 aggregates act as self-templating seeds, propagating pathology through the central nervous system via a prion-like cascade. We developed a robust TDP-43 seeding platform for quantitative, high-throughput assessment of TDP-43 aggregate uptake, cell-to-cell spreading and direct quantification of TDP-43 nuclear function within living cells, while they progress towards pathology. We show that both patient-derived and recombinant TDP-43 pathological aggregates are abundantly internalized in human neuron-like cells, efficiently recruit endogenous TDP-43 and form cytoplasmic inclusions reminiscent of ALS/FTD pathology. These neoaggregates progressively drive the nuclear egress of TDP-43 leading to its loss of function. The scope of this project is to identify the signatures involved in the progressive egress of TDP-43 from the nucleus to the cytoplasm.

2025-02-20 | GSE285224 | GEO

RNA-seq from USP10 and TDP-43 overexpression and TDP-43 knockdown associated with or without USP10 overexpression in HeLa cells

Project description:We performed RNA-seq on HeLa cells to assess the shared transcriptomics changes between USP10 and TDP-43 overexpression, as well as to understand the effect of USP10 overexpression on TDP-43 loss-of-function targets.

2025-09-21 | E-MTAB-15564 | biostudies-arrayexpress

Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration

Project description:Aberrant aggregation of the prion-like RNA-binding protein TDP-43 drives several fatal neurodegenerative proteinopathies, including amyotrophic lateral sclerosis (ALS). Here, we define how short, specific RNAs solubilize TDP-43. These short RNAs engage and stabilize the TDP-43 RNA-recognition motifs, which allosterically destabilizes a conserved helical region in the prion-like domain, thereby promoting aggregation-resistant conformers. Sequence-space mining identified short RNA chaperones with enhanced activity against TDP-43 and disease-linked variants. Enhanced short RNA chaperones mitigate aberrant TDP-43 phenotypes in optogenetic models and in ALS patient–derived and control motor neurons. In mice experiencing cytoplasmic TDP-43 aggregation and motor neuron loss, an enhanced short RNA chaperone reduces pathological aggregation, restores TDP-43 function, and confers neuroprotection. These findings define a mechanistic and therapeutic framework for RNA-based strategies to counter TDP-43 proteinopathies.

2026-05-15 | PXD071117 | Pride

Progranulin insufficiency and TDP-43 overexpression interact to worsen FTD-related phenotypes in mice.

Project description:Progranulin (GRN) mutations, which typically cause progranulin haploinsufficiency, cause frontotemporal dementia with TDP-43 pathology (FTD-TDP). It is not clear how progranulin insufficiency may cause FTD-TDP. Progranulin-insufficient mice develop FTD-related phenotypes without robust TDP-43 pathology, so we crossed crossed Grn+/- mice (RRID:MMRRC_036771-JAX) with transgenic mice expressing wild-type human TDP-43 (RRID:IMSR_JAX:012836) to investigate the effect of progranulin insufficiency on TDP-43 aggregation and TDP-43–related phenotypes.

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TDP-43 regulates cancer-associated microRNAs

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

TDP-43 seeding induces cytoplasmic aggregation heterogeneity and nuclear loss-of-function of TDP-43

Project description:Cytoplasmic aggregation and nuclear depletion of TDP-43 are hallmarks of several age-related neurodegenerative disorders. Yet, recapitulating both features in cellular systems has been a major challenge. Here, we produced amyloid-like fibrils from the recombinant low-complexity-domain of TDP-43, and demonstrate that sonicated fibrils trigger TDP-43 pathology in human cell lines and iPSC-derived neurons. Fibril-induced cytoplasmic TDP-43 inclusions acquire distinct biophysical properties, recapitulate pathological hallmarks such as phosphorylation, ubiquitin- and p62-accumulation, and recruit nuclear endogenous TDP-43 leading to nuclear-loss-of-function-driven disease-specific cryptic splicing defects. Cytoplasmic TDP-43 aggregates exhibit, with time, distinct heterogeneous morphologies as in patients including compacted, filamentous or fragmented, through the activation of cellular protein clearance pathways. Cell-specific progressive toxicity is provoked by seeded TDP-43 pathology in human neurons. These findings identify templated aggregation of TDP-43 as a key mechanism driving both cytoplasmic gain- and nuclear-loss-of-function, offering a valuable approach to identify modifiers of sporadic TDP-43 proteinopathies.

2025-03-28 | GSE284828 | GEO

Seeded aggregation of TDP-43 induces its loss of function

Project description:Neurodegeneration in ALS and FTD results from both gain of toxicity and loss of normal function of the RNA-binding protein TDP-43, but their mechanistic connection remains unclear. Increasing evidence suggests that TDP-43 aggregates act as self-templating seeds, propagating pathology through the central nervous system via a prion-like cascade. We developed a robust TDP-43 seeding platform for quantitative, high-throughput assessment of TDP-43 aggregate uptake, cell-to-cell spreading and loss of function within living cells, while they progress towards pathology. We show that both patient-derived and recombinant TDP-43 pathological aggregates were abundantly internalized in human neuron-like cells, efficiently recruited endogenous TDP-43 and formed cytoplasmic inclusions reminiscent of ALS/FTD pathology. These neoaggregates progressively drove the nuclear egress of TDP-43 leading to its loss of function. Our model demonstrates the link between TDP-43 aggregation and aberrant cryptic splicing and provides new tools to identify genetic or pharmacologic modifiers of each step in the process.

2025-04-14 | PXD058981 | Pride

TDP-43 Interactor and Motor Neuron Tagged Ribosome Affinity Purification in a Drosophila Model of ALS

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.

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