PXD017115

PXD017115 is an original dataset announced via ProteomeXchange.

Title	Mutant huntingtin stalls ribosomes and represses protein synthesis independent of fragile X mental retardation protein
Description	Ribosomes translocate one codon at a time in mRNA during protein synthesis, but the regulators of ribosome translocation and their impact on neurodegenerative disease remain poorly understood. Here, we show that huntingtin (Htt) and its poly-Q expanded form, mHtt, a cause of Huntington disease (HD), promotes ribosome stalling and suppresses protein synthesis in vivo and in vitro. We found that fragile mental retardation protein (FMRP), a known promoter of ribosome stalling, is upregulated in HD cells and patients’ tissue. Unexpectedly, FMRP depletion fails to reverse mHtt-mediated ribosome stalling in HD cells. mHtt binds directly to ribosomes in a RNase-sensitive manner and interacts with ribosomal proteins. Combining high-resolution ribosome footprint profiling (Ribo-Seq) and RNA-Seq, we provide a global snapshot of stalling on mRNA transcripts, with a shift in ribosome occupancy toward the 5’ and 3’ end and single-codon unique pauses in HD cells. We also found ribosomes that appear to have stalled in mHtt mRNA before CAG repeat expansion. Thus, Htt regulates protein synthesis via ribosome stalling mechanisms and in turn may affect mRNA elongation, which may be exploited for HD therapeutics.
HostingRepository	PRIDE
AnnounceDate	2021-04-06
AnnouncementXML	Submission_2021-04-06_02:51:28.772.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD017115
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	gogce crynen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Deamidated; Oxidation; monohydroxylated residue; Carbamidomethyl; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2020-01-15 02:29:37	ID requested
⏵ 1	2021-04-06 02:51:29	announced

Eshraghi M, Karunadharma PP, Blin J, Shahani N, Ricci EP, Michel A, Urban NT, Galli N, Sharma M, Ram, í, rez-Jarqu, í, n UN, Florescu K, Hernandez J, Subramaniam S, Mutant Huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease. Nat Commun, 12(1):1461(2021) [pubmed]

submitter keyword: protein synthesis, ribosome, fragile X, huntingtin

Srinivasa Subramaniam
contact affiliation	Neuroscience Deaprtment, The Scripps Reasearch Institute, FL
contact email	SSubrama@scripps.edu
lab head
gogce crynen
contact affiliation	The scripps research institute
contact email	gcrynen@scripps.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD017115
     1. Label: PRIDE project
     2. Name: Mutant huntingtin stalls ribosomes and represses protein synthesis independent of fragile X mental retardation protein