Dataset Information

PrP concentration in the central nervous system: regional variability, genotypic effects, and pharmacodynamic impact

ABSTRACT: 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.

ORGANISM(S): Homo Sapiens Rattus Norvegicus

SUBMITTER: Eric Kuhn

PROVIDER: PXD031432 | panorama | Mon Feb 28 00:00:00 GMT 2022

REPOSITORIES: PanoramaPublic

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Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS.

Mortberg Meredith A MA Zhao Hien T HT Reidenbach Andrew G AG Gentile Juliana E JE Kuhn Eric E O'Moore Jill J Dooley Patrick M PM Connors Theresa R TR Mazur Curt C Allen Shona W SW Trombetta Bianca A BA McManus Alison A Moore Matthew R MR Liu Jiewu J Cabin Deborah E DE Kordasiewicz Holly B HB Mathews Joel J Arnold Steven E SE Vallabh Sonia M SM Minikel Eric Vallabh EV

JCI insight 20220322 6

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 6 species of interest and applicable to brain and cerebrospinal fluid (CSF). PrP concentration varied dramatically acros ...[more]

PMID: 35133987

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Dataset Information

PrP concentration in the central nervous system: regional variability, genotypic effects, and pharmacodynamic impact

Publications

Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS.

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