PXD076487-1

PXD076487 is an original dataset announced via ProteomeXchange.

Title	A self-complementary recombinant adeno-associated virus vector coding for an anchorless prion protein carrying the G127V mutation extends survival in a rodent prion disease model
Description	The replacement of a single codon in the human prion gene, causing the substitution of glycine with valine at position 127 (G127V) of the prion protein (PrP), prevents development of prion disease. We set out to explore if prion disease survival extension manifests in mice if the V127 mutant is delivered through a recombinant adeno-associated virus (rAAV) packaged as a self-complementary DNA. The notorious delivery limitations of rAAVs were overcome using a cross-correction approach that relied on the expression of the mutation in the context of glycosylphosphatidylinositoI-anchorless (ΔGPI) PrP. In this proof-of-concept study, we inoculated Rocky Mountain Laboratory (RML) prions into knock-in mice, in which the endogenous murine prion protein gene (Prnp) was replaced with the bank vole prion protein gene (BvPrnp). Prion-inoculated mice that were retro-orbitally transduced with a protective rAAV vector encoding BvPrnpV127ΔGPI survived ~50 days longer than control mice that were unprotected. A deep proteomic analysis revealed that BvPrnpV127ΔGPI was protective by slowing perturbations to the proteome observed in late-stage RML prion disease. In addition to capturing details of synaptic decay and depletion of proteins in proximity to PrP, the proteomic dataset revealed the identity of proteins of potential diagnostic value that may be central to the brain’s attempt to fight prion disease by contributing to astrocytosis or microgliosis, by coping with calcium influx, or by enhancing the endoplasmic reticulum processing of essential proteins. Taken together, our results demonstrate that a gene therapy based on a GPI-anchorless PrP containing the G127V mutation can delay the onset of prion disease in mice, providing a framework for development of a corresponding therapy in humans.
HostingRepository	PRIDE
AnnounceDate	2026-07-28
AnnouncementXML	Submission_2026-07-27_22:26:15.516.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	cunjie zhang
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	iodoacetamide derivatized residue
Instrument	orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2026-04-02 00:49:33	ID requested
⏵ 1	2026-07-27 22:26:16	announced

Dataset with its publication pending

submitter keyword: mouse brain, prion, LC-MS(DIA)

Gerold Schmitt-Ulms
contact affiliation	Tanz Centre for Research in Neurodegenerative Diseases, and Department of Laboratory Medicine and Pathobiology University of Toronto
contact email	g.schmittulms@utoronto.ca
lab head
cunjie zhang
contact affiliation	university of Toronto
contact email	cunjie.zhang@utoronto.ca
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD076487
     1. Label: PRIDE project
     2. Name: A self-complementary recombinant adeno-associated virus vector coding for an anchorless prion protein carrying the G127V mutation extends survival in a rodent prion disease model