ArticleProceedings of the National Academy of Sciences of the United States of America2013
Drug resistance confounding prion therapeutics.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 94 papers.
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Who cites it
94 citing papers in PubMed, 157 citations in OpenAlex.
- Life at the interface: Byron Caughey's search for prion disease inhibitors through chemistry, structure, and cell physiology.Acta neuropathologica · 2026Review
- Article
- The protein disulfide isomerase P4HB/PDIA1 modulates cellular and misfolded forms of the prion protein.PLoS pathogens · 2026Article
- De novo formation of familial Alzheimer's disease-relevant Aβ strains occurs exclusively in the human brain.Acta neuropathologica communications · 2026Article
- Adaptation of α-synuclein fibrils following multiple system atrophy transmission to mice.bioRxiv : the preprint server for biology · 2026Article
- Enhanced lysosomal activity prevents infection with PrPThe Journal of biological chemistry · 2026Article
- Genome-wide screens identify core regulators of cell surface prion protein expression.Scientific reports · 2026Article
- Oligosaccharyltransferase (OST) complex inhibition effectively treats rodent and human prions.PLoS pathogens · 2026Article
- One organelle to rule them all: enhancement of lysosomal activity as a therapeutic modality for protein misfolding neurodegenerative diseases.Frontiers in neuroscience · 2026Review
- Review
- Tauopathy strains differentially replicate in vitro in the presence of mutant tau monomer.Neurobiology of disease · 2025Article
- Evidence of a novel α-synuclein strain isolated from a Parkinson's disease with dementia patient sample.Acta neuropathologica communications · 2025Article
- Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism.JCI insight · 2025Article
- In vivo base editing extends lifespan of a humanized mouse model of prion disease.Nature medicine · 2025Article
- Limitations and Applications of Rodent Models in Tauopathy and Synucleinopathy Research.Journal of neurochemistry · 2025Review
- Therapeutic effect of curcumin derivative GT863 on prion-infected mice.Scientific reports · 2025Article
- Investigating the In Vivo Effects of Anti-Prion Protein Nanobodies on Prion Disease with AAV Vector.Pathogens (Basel, Switzerland) · 2025Article
- Therapeutic Trajectories in Human Prion Diseases.Sub-cellular biochemistry · 2025Review
- Reactive Microglia and Astrocytes as Therapeutic Targets in Prion Diseases.Sub-cellular biochemistry · 2025Review
- Therapeutic perspectives for prion diseases in humans and animals.PLoS pathogens · 2024Article
34 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
There is not a single pharmaceutical that halts or even slows any neurodegenerative disease. Mounting evidence shows that prions cause many neurodegenerative diseases, and arguably, scrapie and Creutzfeldt-Jakob disease prions represent the best therapeutic targets. We report here that the previously identified 2-aminothiazoles IND24 and IND81 doubled the survival times of scrapie-infected, wild-type mice. However, mice infected with Rocky Mountain Laboratory (RML) prions, a scrapie-derived strain, and treated with IND24 eventually exhibited neurological dysfunction and died. We serially passaged their brain homogenates in mice and cultured cells. We found that the prion strain isolated from IND24-treated mice, designated RML[IND24], emerged during a single passage in treated mice. Although RML prions infect both the N2a and CAD5 cell lines, RML[IND24] prions could only infect CAD5 cells. When passaged in CAD5 cells, the prions remained resistant to high concentrations of IND24. However, one passage of RML[IND24] prions in untreated mice restored susceptibility to IND24 in CAD5 cells. Although IND24 treatment extended the lives of mice propagating different prion strains, including RML, another scrapie-derived prion strain ME7, and chronic wasting disease, it was ineffective in slowing propagation of Creutzfeldt-Jakob disease prions in transgenic mice. Our studies demonstrate that prion strains can acquire resistance upon exposure to IND24 that is lost upon passage in mice in the absence of IND24. These data suggest that monotherapy can select for resistance, thus intermittent therapy with mixtures of antiprion compounds may be required to slow or stop neurodegeneration.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.