Modulation of prion protein expression through cryptic splice site manipulation.

Autor:	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.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2024 Aug; Vol. 300 (8), pp. 107560. Date of Electronic Publication: 2024 Jul 11.
DOI:	10.1016/j.jbc.2024.107560
Abstrakt:	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. Competing Interests: Conflict of interest S. M. V. acknowledges speaking fees from Ultragenyx, Illumina, Biogen, and Eli Lilly, consulting fees from Invitae and Alnylam, and research support from Ionis, Gate, and Sangamo. E.V.M. acknowledges speaking fees from Eli Lilly, consulting fees from Deerfield and Alnylam, and research support from Ionis, Gate, and Sangamo. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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