Year: 2017
Type: preprint
Abstract: The prototypical PrP prion diseases are invariably fatal, and the search for agents to treat them spans more than 30 years, with limited success.However, in the last few years, the application of high-throughput screening, medicinal chemistry, and pharmacokinetic optimization has led to important advances.The PrP prion inoculation paradigm provides a robust assay for testing therapeutic efficacy, and a dozen compounds have been reported that lead to meaningful extension in survival of prion-infected mice.Here, we review the history and recent progress in the field, focusing on studies validated in animal models.Based on screens in cells infected with mouse-passaged PrP prions, orally available compounds were generated that double or even triple the survival of mice infected with the same prion strain.Unfortunately, no compounds have yet shown efficacy against human prions.Nevertheless, the speed of the recent advances brings hope that an effective therapeutic can be developed.A successful treatment for any neurodegenerative disease would be a major achievement, and the growing understanding that the more common neurodegenerative diseases, including Alzheimer's and Parkinson's, progress by an analogous prion mechanism serves to highlight the importance of antiprion therapeutics. BACKGROUND Human PrP Prion DiseasesT he prototypical PrP prion diseases are rap- idly progressive and fatal neurodegenerative disorders.They are caused by the conformational change of the cellular prion protein (PrP C ) into an alternative form, termed PrP Sc , which then templates further misfolding of PrP C .This induced conformational self-propagation is now understood to play a central role in many neurodegenerative diseases including Alzheimer's and Parkinson's (Prusiner 2012;Walker and Jucker 2015).Unique among neurodegenerative disorders, PrP prion diseases are also found in commercially important animal species, including scrapie in sheep, chronic wasting disease (CWD) in deer, and bovine spongiform encephalopathy (BSE) in cattle.Most human PrP prion diseases have no clear origin and are considered sporadic.They occur from an initial stochastic conversion of PrP C to PrP Sc , which typically leads to sporadic Creutzfeldt-Jakob disease (sCJD).A polymor-
Institution: University of California, San Francisco
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2575248267