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Modulation of prion protein expression through cryptic splice site manipulation.
Gentile, Juliana E; Corridon, Taylor L; Mortberg, Meredith A; D'Souza, Elston Neil; Whiffin, Nicola; Minikel, Eric Vallabh; Vallabh, Sonia M.
Afiliación
  • Gentile JE; McCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Corridon TL; McCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Mortberg MA; McCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • D'Souza EN; Big Data Institute and Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Whiffin N; Big Data Institute and Centre for Human Genetics, University of Oxford, Oxford, UK; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Minikel EV; McCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Vallabh SM; McCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Electronic address: svallabh@broadinstitute.org.
J Biol Chem ; 300(8): 107560, 2024 Aug.
Article en En | MEDLINE | ID: mdl-39002681
ABSTRACT
Lowering expression of prion protein (PrP) is a well-validated therapeutic strategy in prion disease, but additional modalities are urgently needed. In other diseases, small molecules have proven capable of modulating pre-mRNA splicing, sometimes by forcing inclusion of cryptic exons that reduce gene expression. Here, we characterize a cryptic exon located in human PRNP's sole intron and evaluate its potential to reduce PrP expression through incorporation into the 5' untranslated region. This exon is homologous to exon 2 in nonprimate species but contains a start codon that would yield an upstream open reading frame with a stop codon prior to a splice site if included in PRNP mRNA, potentially downregulating PrP expression through translational repression or nonsense-mediated decay. We establish a minigene transfection system and test a panel of splice site alterations, identifying mutants that reduce PrP expression by as much as 78%. Our findings nominate a new therapeutic target for lowering PrP.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Exones / Sitios de Empalme de ARN / Proteínas Priónicas Límite: Animals / Humans Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Exones / Sitios de Empalme de ARN / Proteínas Priónicas Límite: Animals / Humans Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos