PrP turnover in vivo and the time to effect of prion disease therapeutics
Corridon, T. L.; O'Moore, J.; Seerley, A.; Sprague, D. A.; Lian, Y.; Kamath, N. G.; Laversenne, V.; Noble, B.; Serack, F. E.; Shaikh, A. B.; Erickson, B.; Braun, C.; DeSouza-Lenz, K.; Howard, M.; Chan, N.; Jackson, W. S.; Reidenbach, A. G.; Cabin, D. E.; Vallabh, S. M.; Grindeland, A.; Oberbeck, N.; Zhao, H. T.; Minikel, E. V.
Show abstract
PrP lowering is effective against prion disease in animal models and is being tested clinically. Therapies in the current pipeline lower PrP production, leaving pre-existing PrP to be cleared according to its own half-life. We hypothesized that PrPs half-life may be a rate-limiting factor for the time to effect of PrP-lowering drugs, and one reason why late treatment of prion-infected mice is not as effective as early treatment. Using isotopically labeled diet with targeted mass spectrometry, as well as antisense oligonucleotide treatment followed by timed PrP measurement, we estimate a half-life of 5-6 days for PrP in the brain. PrP turnover is not affected by over- or under-expression. Mouse PrP and human PrP have similar turnover rates measured in wild-type or humanized knock-in mice. CSF PrP appears to mirror brain PrP in real time in rats. PrP is more readily quantifiable in colon than in other peripheral organs, and appears to have a shorter half-life in colon than in brain. An under-expressed pathogenic mutant PrP, corresponding to D178N in humans, exhibits an accelerated turnover rate. Our data may inform the design of both preclinical and clinical studies of PrP-lowering drugs.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Cell type-specific biotin labeling in vivo resolves regional neuronal proteomic differences in mouse brain 95%
- Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers 95%
- Elevated synaptic PKA activity and abnormal striatal dopamine signaling in Akap11 mutant mice, a genetic model of schizophrenia and bipolar disorder 94%
Similar papers in this journal
Similar papers in this journal
- β-Amyloid Induces Microglial Expression of GPC4 and APOE Leading to Increased Neuronal Tau Pathology and Toxicity 95%
- APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology 94%
- Multi-modal Proteomic Characterization of Lysosomal Function and Proteostasis in Progranulin-Deficient Neurons 94%
Similar papers in this journal
- Neither alpha-synuclein-preformed fibrils derived from patients with GBA1 mutations nor the host murine genotype significantly influence seeding efficacy in the mouse olfactory bulb. 95%
- Novel tools to quantify total, phospho-Ser129 and aggregated alpha-synuclein in the mouse brain 94%
- A topographical atlas of alpha-Synuclein dosage and cell-type expression in the mouse brain and periphery 94%
Similar papers in this journal
- Partial inhibition of mitochondrial complex I attenuates neurodegeneration and restores energy homeostasis and synaptic function in a symptomatic Alzheimers mouse model 95%
- Lewy-MSA hybrid fold drives distinct neuronal a-synuclein pathology 94%
- Post-ischemic ubiquitination at the postsynaptic density reversibly influences the activity of ischemia-relevant kinases 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.