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Sökning: id:"swepub:oai:DiVA.org:liu-202235" > Anti-prion drugs do...

  • Walsh, Daniel J.Geisel Sch Med Dartmouth, NH 03755 USA (författare)

Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease

  • Artikel/kapitelEngelska2024

Förlag, utgivningsår, omfång ...

  • PUBLIC LIBRARY SCIENCE,2024
  • printrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:liu-202235
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-202235URI
  • https://doi.org/10.1371/journal.ppat.1012087DOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • Funding Agencies|National Institute for Neurological Diseases and Stroke [R37NS125431, R01NS117276, R01NS118796]; National Institutes of Health [P20-GM113132]
  • Prion diseases uniquely manifest in three distinct forms: inherited, sporadic, and infectious. Wild-type prions are responsible for the sporadic and infectious versions, while mutant prions cause inherited variants like fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). Although some drugs can prolong prion incubation times up to four-fold in rodent models of infectious prion diseases, no effective treatments for FFI and fCJD have been found. In this study, we evaluated the efficacy of various anti-prion drugs on newly-developed knock-in mouse models for FFI and fCJD. These models express bank vole prion protein (PrP) with the pathogenic D178N and E200K mutations. We applied various drug regimens known to be highly effective against wild-type prions in vivo as well as a brain-penetrant compound that inhibits mutant PrPSc propagation in vitro. None of the regimens tested (Anle138b, IND24, Anle138b + IND24, cellulose ether, and PSCMA) significantly extended disease-free survival or prevented mutant PrPSc accumulation in either knock-in mouse model, despite their ability to induce strain adaptation of mutant prions. Our results show that anti-prion drugs originally developed to treat infectious prion diseases do not necessarily work for inherited prion diseases, and that the recombinant sPMCA is not a reliable platform for identifying compounds that target mutant prions. This work underscores the need to develop therapies and validate screening assays specifically for mutant prions, as well as anti-prion strategies that are not strain-dependent. We treated two mouse models of inherited prion disease with a variety of drug treatments, including several which have been previously shown to be highly effective against infectious prion diseases and another that biochemically inhibits the formation of mutant prion proteins in a test tube assay. Surprisingly none of the treatments improved lifespans in the either mouse model even though several treatments changed the distribution pattern of prion pathology in the brains of treated mice. Our results show that alternative strategies are needed to develop treatments for inherited prion diseases.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Rees, Judy R.Geisel Sch Med Dartmouth, NH USA (författare)
  • Mehra, SurabhiUniv Toronto, Canada (författare)
  • Bourkas, Matthew E. C.Univ Toronto, Canada (författare)
  • Kaczmarczyk, LechLinköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten,Wallenberg Center for Molecular Medicine(Swepub:liu)lecka48 (författare)
  • Stuart, EricaUniv Toronto, Canada (författare)
  • Jackson, WalkerLinköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten,Wallenberg Center for Molecular Medicine(Swepub:liu)walja90 (författare)
  • Watts, Joel C.Univ Toronto, Canada; Univ Toronto, Canada (författare)
  • Supattapone, SurachaiGeisel Sch Med Dartmouth, NH 03755 USA (författare)
  • Geisel Sch Med Dartmouth, NH 03755 USAGeisel Sch Med Dartmouth, NH USA (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:PLoS Pathogens: PUBLIC LIBRARY SCIENCE20:41553-73661553-7374

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