PXD005120

PXD005120 is an original dataset announced via ProteomeXchange.

Title	Huntingtin inclusions trigger cellular quiescence, deactivate apoptosis and lead to delayed necrosis
Description	Two popular models for how mutant Huntingtin exon 1 (Httex1) aggregation into inclusions relates to pathogenesis involve seemingly contradictory mechanisms. In one model, inclusions are adaptive by sequestering the proteotoxicity of soluble Httex1. In the other, inclusions compromise cellular activity from proteome co-aggregation. Via a biosensor of Httex1 conformation in mammalian cell models, we discovered a mechanism that explains this contradiction. Newly-formed inclusions are comprised of disordered Httex1 and ribonucleoproteins. As inclusions matured, Httex1 reconfigured into amyloid, and other glutamine-rich and prion-domain containing proteins were recruited. Soluble Httex1 caused a hyperpolarized mitochondrial membrane potential, increased reactive oxygen species and promoted apoptosis. Inclusion formation triggered a collapsed mitochondrial potential, cellular quiescence, and deactivated apoptosis. We propose a revised model where both soluble Httex1 and inclusions are toxic, yet inclusions impair programmed cell death arising from stalled cellular functioning. Hence cells live longer in a metabolically quiescent state and ultimately die by necrosis.
HostingRepository	PRIDE
AnnounceDate	2017-05-04
AnnouncementXML	Submission_2017-05-04_08:12:39.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mikhail Trubetskov
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2016-10-10 01:58:18	ID requested
⏵ 1	2017-05-04 08:12:40	announced

Ramdzan YM, Trubetskov MM, Ormsby AR, Newcombe EA, Sui X, Tobin MJ, Bongiovanni MN, Gras SL, Dewson G, Miller JML, Finkbeiner S, Moily NS, Niclis J, Parish CL, Purcell AW, Baker MJ, Wilce JA, Waris S, Stojanovski D, B, ö, cking T, Ang CS, Ascher DB, Reid GE, Hatters DM, Huntingtin Inclusions Trigger Cellular Quiescence, Deactivate Apoptosis, and Lead to Delayed Necrosis. Cell Rep, 19(5):919-927(2017) [pubmed]

curator keyword: Biomedical

submitter keyword: Huntingtin, Huntington's disease, aggregation, inclusion, apoptosis, mechanism of death

Danny M. Hatters
contact affiliation	Department of Biochemistry and Molecular Biology; and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, VIC 3010. Australia
contact email	dhatters@unimelb.edu.au
lab head
Mikhail Trubetskov
contact affiliation	University of Melbourne
contact email	mtrubetskov@student.unimelb.edu.au
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/2017/05/PXD005120

PRIDE project URI

• PRIDE
  1. PXD005120
     1. Label: PRIDE project
     2. Name: Huntingtin inclusions trigger cellular quiescence, deactivate apoptosis and lead to delayed necrosis