PXD010966

PXD010966 is an original dataset announced via ProteomeXchange.

Title	FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy
Description	Unraveling the mechanistic link connecting the multiple RNA-binding proteins (RBPs) associated with amyotrophic lateral sclerosis (ALS) is critical for identifying novel therapeutics. Mutations in the RBP FUS cause the third most common genetic form of ALS. Here, we show that motor neurons (MNs) of FUS-ALS patients manifest heterogeneous levels of cytoplasmic FUS. Using neurons differentiated from induced pluripotent stem cells (iPSCs) carrying a FUS-eGFP reporter, we demonstrate that pronounced cytoplasmic FUS mislocalization is linked to aberrant protein degradation. We also show that the P525L FUS mutation reduces the interaction of FUS with RBPs, including hnRNPA1, hnRNPA2B1, EWSR1, and TAF15, facilitating FUS aggregation. Additionally, RBP levels are decreased, inducing neurodegeneration. We use patient spinal cord to demonstrate that MNs containing aggregated FUS have reduced RBP content compared to MNs lacking FUS aggregates. Finally, we demonstrate that small molecules inducing autophagy, including PQR309, a brain penetrant compound in clinical trials, restore proteostasis.
HostingRepository	PRIDE
AnnounceDate	2019-03-26
AnnouncementXML	Submission_2019-03-26_02:13:17.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Hannes Drexler
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2018-08-31 03:27:57	ID requested
⏵ 1	2019-03-26 02:13:18	announced

Dataset with its publication pending

curator keyword: Biomedical

submitter keyword: Amyotrophic lateral sclerosis, ALS, FUS, induced pluripotent stem cells, RNA-binding proteins, proteostasis, autophagy, proteomics, LC-MSMS, label free quantification

Hannes C. A. Drexler
contact affiliation	Bioanalytical Mass Spectrometry, Max Planck Institute for Molecular Biomedicine, Röntgenstr. 20, 48149 Münster, Germany
contact email	hannes.drexler@mpi-muenster.mpg.de
lab head
Hannes Drexler
contact affiliation	Bioanalytical Mass Spectrometry
contact email	hannes.drexler@mpi-muenster.mpg.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/2019/03/PXD010966

PRIDE project URI

• PRIDE
  1. PXD010966
     1. Label: PRIDE project
     2. Name: FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy