PXD031432-3

PXD031432 is an original dataset announced via ProteomeXchange.

Title	PrP concentration in the central nervous system: regional variability, genotypic effects, and pharmacodynamic impact
Description	Prion protein (PrP) concentration controls the kinetics of prion replication and is a genetically and pharmacologically validated therapeutic target for prion disease. In order to evaluate PrP concentration as a pharmacodynamic biomarker and assess its contribution to known prion disease risk factors, we developed and validated a plate-based immunoassay reactive for PrP across six species of interest and applicable to brain and cerebrospinal fluid (CSF). PrP concentration varies dramatically between different brain regions in mice, cynomolgus macaques, and humans. PrP expression does not appear to contribute to the known risk factors of age, sex, or common PRNP genetic variants. CSF PrP is lowered in the presence of rare pathogenic PRNP variants, with heterozygous carriers of P102L displaying 55% and of D178N just 31% the CSF PrP concentration of mutation-negative controls. In rodents, pharmacologic reduction of brain Prnp RNA is reflected in brain parenchyma PrP, and in turn in CSF PrP, validating CSF as a sampling compartment for the effect of PrP-lowering therapy. Our findings support the use of CSF PrP as a pharmacodynamic biomarker for PrP-lowering drugs, and suggest that relative reduction from individual baseline CSF PrP concentration may be an appropriate marker for target engagement.
HostingRepository	PanoramaPublic
AnnounceDate	2022-02-28
AnnouncementXML	Submission_2022-02-28_16:49:41.846.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	supported by repository but incomplete data and/or metadata
PrimarySubmitter	Eric Kuhn
SpeciesList	scientific name: Rattus norvegicus; NCBI TaxID: 10116; scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	Carbamidomethyl; Oxidation; Label:15N(1); Label:13C(6)15N(4); Label:15N(2); Label:13C(6)15N(2); Label:15N(4); Label:15N(3)
Instrument	TSQ Quantiva

Revision	Datetime	Status	ChangeLog Entry
0	2022-02-03 19:26:54	ID requested
1	2022-02-07 16:58:10	announced
2	2022-02-08 13:14:52	announced	: Added publication
⏵ 3	2022-02-28 16:49:42	announced	: Added PubMed Id

Mortberg MA, Zhao HT, Reidenbach AG, Gentile JE, Kuhn E, O'Moore J, Dooley PM, Connors TR, Mazur C, Allen SW, Trombetta BA, McManus A, Moore MR, Liu J, Cabin DE, Kordasiewicz HB, Mathews J, Arnold SE, Vallabh SM, Minikel EV, Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS. JCI Insight, 7(6):(2022) [pubmed]

submitter keyword: cerebrospinal fluid, LC-MRM-MS, TSQ Quantiva, Skyline, antisense oligonucleotide, prion protein

Steve Carr
contact affiliation	The Broad Institute
contact email	scarr@broad.mit.edu
lab head
Eric Kuhn
contact affiliation	Broad Institute
contact email	ekuhn@broadinstitute.org
dataset submitter

Panorama Public dataset URI