PXD004744

PXD004744 is an original dataset announced via ProteomeXchange.

Title	TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons - Surface labelling
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.
HostingRepository	PRIDE
AnnounceDate	2021-03-04
AnnouncementXML	Submission_2021-03-04_12:17:59.650.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Stephan Mueller
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2016-08-10 02:49:39	ID requested
⏵ 1	2021-03-04 12:18:00	announced

Schwenk BM, Hartmann H, Serdaroglu A, Schludi MH, Hornburg D, Meissner F, Orozco D, Colombo A, Tahirovic S, Michaelsen M, Schreiber F, Haupt S, Peitz M, Br, ü, stle O, K, ü, pper C, Klopstock T, Otto M, Ludolph AC, Arzberger T, Kuhn PH, Edbauer D, TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons. EMBO J, 35(21):2350-2370(2016) [pubmed]

curator keyword: Biological

submitter keyword: TDP-43, recycling endosomes, ErbB4, FTLD, ALS, surface labelling

Dieter Edbauer
contact affiliation	German Center for Neurodegenerative Diseases (DZNE) Feodor-Lynen-Str. 17 81377 München Germany
contact email	dieter.edbauer@dzne.de
lab head
Stephan Mueller
contact affiliation	DZNE Munich Neuroproteomics
contact email	stephan.mueller@dzne.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/09/PXD004744

PRIDE project URI

• PRIDE
  1. PXD004744
     1. Label: PRIDE project
     2. Name: TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons - Surface labelling