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TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons

ABSTRACT: Whole proteome quantification identified upregulation of the ESCRT component VPS4B upon TDP-43 knockdown in neurons.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Neuron, Cell Culture

DISEASE(S): Disease Free

SUBMITTER: Mario Oroshi

LAB HEAD: Felix Meissner

PROVIDER: PXD004756 | Pride | 2016-09-29

REPOSITORIES: Pride

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			Action	DRS
	20131002_EXQ8_DaHo_SA_Eddi_emptyVector_1.raw	Raw
	20131002_EXQ8_DaHo_SA_Eddi_emptyVector_2.raw	Raw
	20131002_EXQ8_DaHo_SA_Eddi_emptyVector_3_131007123438.raw	Raw
	20131002_EXQ8_DaHo_SA_Eddi_library1_1.raw	Raw
	20131002_EXQ8_DaHo_SA_Eddi_library1_2.raw	Raw

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TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons.

Schwenk Benjamin M BM Hartmann Hannelore H Serdaroglu Alperen A Schludi Martin H MH Hornburg Daniel D Meissner Felix F Orozco Denise D Colombo Alessio A Tahirovic Sabina S Michaelsen Meike M Schreiber Franziska F Haupt Simone S Peitz Michael M Brüstle Oliver O Küpper Clemens C Klopstock Thomas T Otto Markus M Ludolph Albert C AC Arzberger Thomas T Kuhn Peer-Hendrik PH Edbauer Dieter D

The EMBO journal 20160912 21

Nuclear clearance of TDP-43 into cytoplasmic aggregates is a key driver of neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but the mechanisms are unclear. Here, we show that TDP-43 knockdown specifically reduces the number and motility of RAB11-positive recycling endosomes in dendrites, while TDP-43 overexpression has the opposite effect. This is associated with delayed transferrin recycling in TDP-43-knockdown neurons and decreased β2-trans ...[more]

PMID: 27621269

Similar Datasets

TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons - Surface labelling

Project description:Nuclear clearance of TDP-43 into cytoplasmic aggregates is a key driver of neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but the mechanisms are unclear. Here, we show that TDP-43 knockdown specifically reduces number and motility of RAB11-positive recycling endosomes in dendrites, while TDP-43 overexpression has the opposite effect. This is associated with delayed transferrin recycling in TDP-43 knockdown neurons and decreased 2-transferrin levels in patient CSF. Whole proteome quantification identified upregulation of the ESCRT component VPS4B upon TDP-43 knockdown in neurons. Luciferase report assays and chromatin immunoprecipitation suggest that TDP-43 represses VPS4B transcription. Preventing VPS4B upregulation or expression of its functional antagonist ALIX restores trafficking of recycling endosomes. Proteomic analysis revealed broad reduction in surface expression of key receptors upon TDP-43 knockdown including ErbB4, the neuregulin 1 receptor. TDP-43 knockdown delays surface delivery of ErbB4. ErbB4 overexpression, but not neuregulin 1 stimulation, prevents dendrite loss upon TDP-43 knockdown. Thus, impaired recycling of ErbB4 and other receptors to the cell surface may contribute to TDP-43 induced neurodegeneration by blocking trophic signaling.

2016-09-29 | PXD004744 | Pride

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 regulates cancer-associated microRNAs

2016-08-02 | GSE85065 | GEO

Identify the specific binding partners of cytosolic TDP-43 WT and TDP-43ΔCR

Project description:To investigate how translation changed as a function of TDP-43 CR loss, mass spectrometry (MS) based approach was performed to monitor the dynamics of TDP-43-associated protein complexes in response to CR deletion using TDP-43 knockout HEK293 cells expressing strep tagged wild type TDP-43 (TDP-43WT) or TDP-43ΔCR mutant.

2022-05-20 | PXD027494 | Pride

TDP-43 iCLIP of SHSY5Y cells

Project description:TDP-43 is an important RNA binding protein. To better understand its binding targets in human neurons, we performed TDP-43 iCLIP on SHSY5Y cells.

2022-02-02 | E-MTAB-11243 | biostudies-arrayexpress

TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons.

Project description:Nuclear clearance of TDP-43 into cytoplasmic aggregates is a key driver of neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but the mechanisms are unclear. Here, we show that TDP-43 knockdown specifically reduces the number and motility of RAB11-positive recycling endosomes in dendrites, while TDP-43 overexpression has the opposite effect. This is associated with delayed transferrin recycling in TDP-43-knockdown neurons and decreased β2-transferrin levels in patient CSF Whole proteome quantification identified the upregulation of the ESCRT component VPS4B upon TDP-43 knockdown in neurons. Luciferase reporter assays and chromatin immunoprecipitation suggest that TDP-43 represses VPS4B transcription. Preventing VPS4B upregulation or expression of its functional antagonist ALIX restores trafficking of recycling endosomes. Proteomic analysis revealed the broad reduction in surface expression of key receptors upon TDP-43 knockdown, including ErbB4, the neuregulin 1 receptor. TDP-43 knockdown delays the surface delivery of ErbB4. ErbB4 overexpression, but not neuregulin 1 stimulation, prevents dendrite loss upon TDP-43 knockdown. Thus, impaired recycling of ErbB4 and other receptors to the cell surface may contribute to TDP-43-induced neurodegeneration by blocking trophic signaling.

| S-EPMC5090220 | biostudies-literature

TDP-43 Neurotoxicity in late D. melanogaster pupae

Project description:The aim of this study is to understand the mechanisms of TDP-43 neurotoxicity. Here, we perform a RNA-Seq analysis in TDP-43 gain-of-fucntion (GOF) , TDP-43 loss-of-function and wild-type late pupae heads (73-90 hours APF) and perform TDP-43 GOF vs wild type and TDP-43 LOF vs wild-type differential expression analysis to show that both mechanisms presents defects in ecdysone receptor (ECR)-dependeint transcriptional program switching, and strongly deregulate expression from the neuronal microtubule associated protien Map205. RNA-seq was performed in two wild-type D.melanogaster biological replicates (Canton S, w1118 ), four biological replicates for TDP-43 (LOF) with two distinct genotypes (dTDP-43Δ142/Df(2R)106,dTDP-43Δ23/Δ142 ) and two TDP-43 GOF biological replicates (act5c>dTDP-43 ).

2013-01-22 | E-GEOD-42844 | biostudies-arrayexpress

TDP-43 Neurotoxicity in late D. melanogaster pupae

2013-01-22 | GSE42844 | GEO

TDP-43 knockdown in primary rat astrocytes

Project description:TDP-43 is an RNA binding protein involved in amyotrophic lateral sclerosis and other neurodegenerative diseases. The purpose of this study was to determine if loss of TDP-43 function leads to accumulation of repetitive element transcripts, double-stranded RNA (dsRNA) and innate immune activation that may be involved in disease pathology. TDP-43 was knocked down in primary rat astrocytes via siRNA, cells were treated with/without ATP (an immune modulator), and polyA RNA-seq was performed to profile gene expression. Immunoprecipitation/RNA-seq was also performed using a dsRNA-specific antibody to identify potential dsRNAs resulting from TDP-43 knockdown.

2019-08-09 | GSE135611 | GEO

Expression profiles of primary cortical neurons after knocking down Tdp-43

Project description:To clarify the functional properties of Tdp-43, we established the differentially expressed alternative exons in Tdp-43-silenced primary cortical neurons by using exon-sensitive microarray technology. We analyzed total RNA of primary motor neuron infected with lentivirus expressing shRNA against mouse Tdp-43 or control. RNA was harvested 11 days after transfection.

2013-04-18 | E-GEOD-46146 | biostudies-arrayexpress

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