أعرض في EDS

Modulation of prion protein expression through cryptic splice site manipulation.

التفاصيل البيبلوغرافية
العنوان: Modulation of prion protein expression through cryptic splice site manipulation.
المؤلفون: Gentile JE; McCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, MA 02114.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142., Corridon TL; McCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, MA 02114.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142., Mortberg MA; McCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, MA 02114.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142., D'Souza EN; Big Data Institute and Centre for Human Genetics, University of Oxford, Oxford OX3 7LF, UK., Whiffin N; Big Data Institute and Centre for Human Genetics, University of Oxford, Oxford OX3 7LF, UK.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA., Minikel EV; McCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, MA 02114.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142., Vallabh SM; McCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, MA 02114.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142.
المصدر: BioRxiv : the preprint server for biology [bioRxiv] 2023 Dec 19. Date of Electronic Publication: 2023 Dec 19.
نوع المنشور: Preprint
اللغة: English
بيانات الدورية: Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
مستخلص: 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 (5'UTR). This exon is homologous to exon 2 in non-primate species, but contains a start codon that would yield an upstream open reading frame (uORF) 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.
التعليقات: Update in: J Biol Chem. 2024 Jul 11;300(8):107560. doi: 10.1016/j.jbc.2024.107560. (PMID: 39002681)
References: Lancet Neurol. 2020 Apr;19(4):361-368. (PMID: 32199098)
Genome Res. 1998 Oct;8(10):1022-37. (PMID: 9799790)
Nucleic Acids Res. 2023 Aug 11;51(14):7109-7124. (PMID: 37188501)
Nature. 2012 May 06;485(7399):507-11. (PMID: 22622579)
Nat Commun. 2020 May 27;11(1):2523. (PMID: 32461616)
Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13363-83. (PMID: 9811807)
Brain Res. 1997 Mar 21;751(2):265-74. (PMID: 9099814)
J Med Chem. 2018 Aug 09;61(15):6501-6517. (PMID: 30044619)
Genes Dev. 1994 Apr 15;8(8):959-69. (PMID: 7926780)
J Mol Med (Berl). 2007 Feb;85(2):149-61. (PMID: 17206408)
Nat Biomed Eng. 2022 Nov;6(11):1272-1283. (PMID: 35902773)
Nature. 2021 May;593(7859):429-434. (PMID: 34012082)
Nat Rev Drug Discov. 2022 Oct;21(10):736-762. (PMID: 35941229)
Nat Commun. 2021 Mar 9;12(1):1515. (PMID: 33750777)
Vet Res. 2012 Dec 18;43:87. (PMID: 23249298)
Trends Biochem Sci. 1998 Jun;23(6):198-9. (PMID: 9644970)
N Engl J Med. 2021 Mar 11;384(10):915-923. (PMID: 33626251)
Nucleic Acids Res. 2020 Nov 4;48(19):10615-10631. (PMID: 32776089)
Am J Hum Genet. 2021 Jun 3;108(6):1083-1094. (PMID: 34022131)
Nat Neurosci. 2010 Mar;13(3):310-8. (PMID: 20098419)
JCI Insight. 2022 Mar 22;7(6):. (PMID: 35133987)
Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6418-22. (PMID: 7912827)
Nature. 1992 Apr 16;356(6370):577-82. (PMID: 1373228)
Mol Med. 1994 Nov;1(1):19-30. (PMID: 8790598)
Proc Natl Acad Sci U S A. 2009 May 5;106(18):7507-12. (PMID: 19372376)
Nat Biotechnol. 2007 Jan;25(1):132-8. (PMID: 17195841)
EMBO J. 2016 Apr 1;35(7):706-23. (PMID: 26896445)
Science. 2020 Sep 11;369(6509):1318-1330. (PMID: 32913098)
J Biol Chem. 2020 Sep 25;295(39):13516-13531. (PMID: 32723867)
Nat Methods. 2012 Jun 28;9(7):676-82. (PMID: 22743772)
Annu Rev Pharmacol Toxicol. 2021 Jan 6;61:831-852. (PMID: 33035446)
Nat Rev Genet. 2023 Apr;24(4):251-269. (PMID: 36526860)
Nucleic Acids Res. 2021 Jan 25;49(2):657-673. (PMID: 33367834)
Genome Res. 2018 Jul;28(7):968-974. (PMID: 29858273)
Nat Biotechnol. 2016 Aug;34(8):875-80. (PMID: 27398791)
Genome Res. 2002 Jun;12(6):996-1006. (PMID: 12045153)
RNA Biol. 2020 Feb;17(2):227-239. (PMID: 31619139)
Science. 2015 May 8;348(6235):666-9. (PMID: 25954003)
Mol Syst Biol. 2014 Aug 28;10:748. (PMID: 25170020)
Nat Chem Biol. 2015 Jul;11(7):511-7. (PMID: 26030728)
Genome Med. 2022 Jul 26;14(1):79. (PMID: 35883178)
PLoS One. 2008;3(12):e3872. (PMID: 19060956)
Science. 2014 Aug 8;345(6197):688-93. (PMID: 25104390)
Sci Transl Med. 2016 Jan 20;8(322):322ra9. (PMID: 26791950)
Nat Chem Biol. 2019 Dec;15(12):1191-1198. (PMID: 31636429)
Pediatr Res. 2011 Nov;70(5):480-3. (PMID: 21775922)
JCI Insight. 2019 Jul 30;5:. (PMID: 31361599)
Nature. 2020 May;581(7809):459-464. (PMID: 32461653)
Nat Commun. 2022 Nov 10;13(1):6797. (PMID: 36357392)
معلومات مُعتمدة: United Kingdom WT_ Wellcome Trust; R01 NS125255 United States NS NINDS NIH HHS
تواريخ الأحداث: Date Created: 20240108 Latest Revision: 20240803
رمز التحديث: 20240804
مُعرف محوري في PubMed: PMC10769280
DOI: 10.1101/2023.12.19.572439
PMID: 38187635
قاعدة البيانات: MEDLINE
الوصف
تدمد:2692-8205
DOI:10.1101/2023.12.19.572439