PXD008417

PXD008417 is an original dataset announced via ProteomeXchange.

Title	DROSOPHILA FUS MUTANT PHENOTYPES ARE MEDIATED BY INCREASED XRP1 EXPRESSION LEADING TO GENE EXPRESSION DYSREGULATION
Description	Several RNA-binding proteins (RBPs) are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), including the FET proteins FUS, TAF15 and EWSR1. Cabeza (caz) is the single Drosophila FET ortholog. Here, we identified Xrp1, a poorly characterized DNA-binding protein, as a key modifier of caz mutant phenotypes. Xrp1 expression was strongly upregulated in caz mutants, and Xrp1 heterozygosity rescued their motor defects and life span. Interestingly, selective neuronal Xrp1 knock-down was sufficient to rescue, and neuronal Xrp1 overexpression phenocopied caz mutant phenotypes. The caz/Xrp1 genetic interaction depended on the functionality of the AT-hook DNA-binding domain in Xrp1. Consistently, caz mutants displayed gene expression dysregulation, which was mitigated by Xrp1 heterozygosity. Finally, Xrp1 knock-down substantially rescued the motor deficits and life span of flies expressing ALS-mutant FUS in motor neurons. Taken together, caz mutant phenotypes are mediated by increased neuronal Xrp1 levels, leading to gene expression dysregulation and neuronal dysfunction.
HostingRepository	PRIDE
AnnounceDate	2018-09-06
AnnouncementXML	Submission_2018-09-19_04:23:55.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Hannes Drexler
SpeciesList	scientific name: Drosophila melanogaster (Fruit fly); NCBI TaxID: 7227;
ModificationList	monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2017-12-11 23:36:42	ID requested
1	2018-09-05 23:53:05	announced
⏵ 2	2018-09-19 04:23:56	announced	Updated publication reference for PubMed record(s): 30209068.

Mallik M, Catinozzi M, Hug CB, Zhang L, Wagner M, Bussmann J, Bittern J, Mersmann S, Kl, ä, mbt C, Drexler HCA, Huynen MA, Vaquerizas JM, Storkebaum E, and mediates its toxicity. J Cell Biol, 217(11):3947-3964(2018) [pubmed]

curator keyword: Biological

submitter keyword: Drosophila, amyotrophic lateral sclerosis, frontotemporal dementia, FUS, gene expression regulation, AT-hook motif

Hannes C. A. Drexler
contact affiliation	Max Planck Institute for Molecular Biomedicine Bioanalytical Mass Spectrometry Unit 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

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PRIDE project URI

• PRIDE
  1. PXD008417
     1. Label: PRIDE project
     2. Name: DROSOPHILA FUS MUTANT PHENOTYPES ARE MEDIATED BY INCREASED XRP1 EXPRESSION LEADING TO GENE EXPRESSION DYSREGULATION