PXD026012-2

PXD026012 is an original dataset announced via ProteomeXchange.

Title	Polyglutamine-mediated ribotoxicity disrupts proteostasis and stress responses in Huntington’s Disease
Description	Huntington’s disease (HD) is a neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat in the Huntingtin (HTT) gene, encoding a homopolymeric polyglutamine (polyQ) tract. Although mutant HTT (mHTT) protein is known to aggregate, the links between aggregation and neurotoxicity remain unclear. Here we show that both translation and aggregation of wild-type and mHTT are regulated by a stress-responsive upstream open reading frame, and that polyQ expansions cause abortive translation termination and release of truncated, aggregation-prone mHTT fragments. Notably, we find that mHTT depletes translation elongation factor eIF5A in brains of symptomatic HD mice and cultured HD cells, leading to pervasive ribosome pausing and collisions. Loss of eIF5A disrupts homeostatic controls and impairs recovery from acute stress. Importantly, drugs that inhibit translation initiation reduce premature termination and mitigate this escalating cascade of ribotoxic stress and dysfunction in HD.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:33:04.171.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ranen Aviner
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive; LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2021-05-14 02:44:25	ID requested
1	2024-03-12 20:15:04	announced
⏵ 2	2024-10-22 06:33:04	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: eIF5A, ribosome collision, ribosome stalling,Huntington's disease, translation, aggregation

Judith Frydman
contact affiliation	Department of Biology, Stanford University, USA
contact email	jfrydman@stanford.edu
lab head
Ranen Aviner
contact affiliation	Chan Zuckerberg Biohub
contact email	ranen.aviner@gmail.com
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/2024/03/PXD026012

PRIDE project URI

• PRIDE
  1. PXD026012
     1. Label: PRIDE project
     2. Name: Polyglutamine-mediated ribotoxicity disrupts proteostasis and stress responses in Huntington’s Disease