PXD023852

PXD023852 is an original dataset announced via ProteomeXchange.

Title	HDAC6 inhibition restores TDP-43 pathology and axonal transport defects in human motor neurons with TARDBP mutations
Description	TDP-43 is the major component of pathological inclusions in most ALS patients and in up to 50% of patients with frontotemporal dementia (FTD). Heterozygous missense mutations in TARDBP, the gene encoding TDP-43, are one of the common causes of familial ALS. In this study, we investigate TDP-43 protein behavior in induced pluripotent stem cell (iPSC)-derived motor neurons from three ALS patients with different TARDBP mutations and three healthy controls. TARDPB mutations induce several TDP-43 changes in spinal motor neurons, including cytoplasmic mislocalization and accumulation of insoluble TDP-43, C-terminal fragments and phospho-TDP-43. By generating iPSC lines with allele-specific tagging of TDP-43, we find that mutant TDP-43 initiates the observed disease phenotypes and has an altered interactome as indicated by mass spectrometry-based proteomics. Our findings also indicate that TDP-43 proteinopathy results in a defect in mitochondrial transport. Lastly, proteomics analyses also show that pharmacological inhibition of histone deacetylase 6 (HDAC6) restores the observed TDP-43 pathologies and the axonal mitochondrial motility, suggesting that HDAC6 inhibition may be an interesting therapeutic target for neurodegenerative disorders linked to TDP-43 pathology.
HostingRepository	PRIDE
AnnounceDate	2021-03-15
AnnouncementXML	Submission_2021-03-15_02:59:59.651.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Rupert Mayer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-01-27 10:46:26	ID requested
⏵ 1	2021-03-15 03:00:00	announced

Fazal R, Boeynaems S, Swijsen A, De Decker M, Fumagalli L, Moisse M, Vanneste J, Guo W, Boon R, Vercruysse T, Eggermont K, Swinnen B, Beckers J, Pakravan D, Vandoorne T, Vanden Berghe P, Verfaillie C, Van Den Bosch L, Van Damme P, HDAC6 inhibition restores TDP-43 pathology and axonal transport defects in human motor neurons with TARDBP mutations. EMBO J, 40(7):e106177(2021) [pubmed]

submitter keyword: TDP-43, interactome, induced pluripotent stem cells, TARDPB mutation, axonal transport, HDAC6, ALS

Philip Van Damme
contact affiliation	KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), B-3000 Leuven, Belgium; VIB, Center for Brain and Disease Research, Laboratory of Neurobiology, Leuven, Belgium; University Hospitals Leuven, Department of Neurology, Leuven, Belgium.
contact email	philip.vandamme@uzleuven.be
lab head
Rupert Mayer
contact affiliation	VIB-UGent Center for Medical Biotechnology, VIB Dpt. for Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University
contact email	rupert.mayer@vib-ugent.be
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/2021/03/PXD023852

PRIDE project URI

• PRIDE
  1. PXD023852
     1. Label: PRIDE project
     2. Name: HDAC6 inhibition restores TDP-43 pathology and axonal transport defects in human motor neurons with TARDBP mutations