1. Modulation of prion protein expression through cryptic splice site manipulation.
- Author
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Gentile, Juliana E., Corridon, Taylor L., Mortberg, Meredith A., D’Souza, Elston Neil, Whiffin, Nicola, Minikel, Eric Vallabh, and Vallabh, Sonia M.
- Subjects
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GENE expression , *SMALL molecules , *PRION diseases , *PROTEIN expression , *TEST systems - Abstract
Lowering expression of prion protein (PrP) is a wellvalidated 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 50 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 nonsensemediated 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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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