PXD022554

PXD022554 is an original dataset announced via ProteomeXchange.

Title	Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration
Description	Alteration to endoplasmic reticulum (ER) proteostasis is observed on a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR-target genes. Here, we designed an ATF6f-XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has stronger effects in reducing the abnormal aggregation of mutant huntingtin and alpha-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson´s and Huntington´s disease. These results support the concept where directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.
HostingRepository	PRIDE
AnnounceDate	2022-09-13
AnnouncementXML	Submission_2022-09-13_11:28:04.312.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jonathan Davies
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2020-11-16 03:39:30	ID requested
⏵ 1	2022-09-13 11:28:05	announced

Vidal RL, Sepulveda D, Troncoso-Escudero P, Garcia-Huerta P, Gonzalez C, Plate L, Jerez C, Canovas J, Rivera CA, Castillo V, Cisternas M, Leal S, Martinez A, Grandjean J, Sonia D, Lashuel HA, Martin AJM, Latapiat V, Matus S, Sardi SP, Wiseman RL, Hetz C, Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the UPR in models of neurodegeneration. Mol Ther, 29(5):1862-1882(2021) [pubmed]

submitter keyword: UPR, XBP1, ATF6, ER stress, protein aggregation, Huntington`s Disease, Parkinson`s Disease

R. Luke Wiseman
contact affiliation	Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
contact email	wiseman@scripps.edu
lab head
Jonathan Davies
contact affiliation	Vanderbilt University
contact email	jonathan.p.davies@vanderbilt.edu
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/2022/09/PXD022554

PRIDE project URI

• PRIDE
  1. PXD022554
     1. Label: PRIDE project
     2. Name: Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration