Regional variability, genotypic effects, and pharmacodynamic impact on prion protein concentration in the central nervous system
Meredith A Mortberg,
Hien T Zhao,
Andrew G Reidenbach,
Juliana E Gentile,
Patrick M. Dooley,
Shona W Allen,
Bianca A Trombetta,
Matthew R Moore,
Deborah E Cabin,
Holly B Kordasiewicz,
Steven E Arnold,
Sonia M Vallabh,
Eric Vallabh Minikel
Posted 01 Nov 2021
medRxiv DOI: 10.1101/2021.11.01.21265619
Posted 01 Nov 2021
Reliable and scalable quantification of prion protein (PrP) is vital to the development of PrP- lowering drugs for prion disease. Here we develop a plate-based immunoassay reactive for PrP across six species of interest and applicable to brain and cerebrospinal fluid (CSF). Brain PrP shows similar patterns of regional variation in mice, cynomolgus macaques and humans. CSF PrP concentration does not appear to differ according to age, sex, or common PRNP variants, but it is reduced in the presence of rare pathogenic PRNP variants, with 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. 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.
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