PMID- 38187635
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240210
DP  - 2023 Dec 19
TI  - Modulation of prion protein expression through cryptic splice site manipulation.
LID - 2023.12.19.572439 [pii]
LID - 10.1101/2023.12.19.572439 [doi]
AB  - 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.
FAU - Gentile, Juliana E
AU  - Gentile JE
AD  - McCance Center for Brain Health and Department of Neurology, Massachusetts 
      General Hospital, Boston, MA 02114.
AD  - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 
      Cambridge, MA 02142.
FAU - Corridon, Taylor L
AU  - Corridon TL
AD  - McCance Center for Brain Health and Department of Neurology, Massachusetts 
      General Hospital, Boston, MA 02114.
AD  - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 
      Cambridge, MA 02142.
FAU - Mortberg, Meredith A
AU  - Mortberg MA
AD  - McCance Center for Brain Health and Department of Neurology, Massachusetts 
      General Hospital, Boston, MA 02114.
AD  - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 
      Cambridge, MA 02142.
FAU - D'Souza, Elston Neil
AU  - D'Souza EN
AD  - Big Data Institute and Centre for Human Genetics, University of Oxford, Oxford 
      OX3 7LF, UK.
FAU - Whiffin, Nicola
AU  - Whiffin N
AUID- ORCID: 0000-0003-1554-6594
AD  - Big Data Institute and Centre for Human Genetics, University of Oxford, Oxford 
      OX3 7LF, UK.
AD  - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 
      Cambridge, MA.
FAU - Minikel, Eric Vallabh
AU  - Minikel EV
AUID- ORCID: 0000-0003-2206-1608
AD  - McCance Center for Brain Health and Department of Neurology, Massachusetts 
      General Hospital, Boston, MA 02114.
AD  - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 
      Cambridge, MA 02142.
FAU - Vallabh, Sonia M
AU  - Vallabh SM
AUID- ORCID: 0000-0003-3824-2702
AD  - McCance Center for Brain Health and Department of Neurology, Massachusetts 
      General Hospital, Boston, MA 02114.
AD  - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 
      Cambridge, MA 02142.
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
GR  - R01 NS125255/NS/NINDS NIH HHS/United States
PT  - Preprint
DEP - 20231219
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
PMC - PMC10769280
EDAT- 2024/01/08 06:42
MHDA- 2024/01/08 06:43
PMCR- 2024/01/05
CRDT- 2024/01/08 04:50
PHST- 2024/01/08 06:42 [pubmed]
PHST- 2024/01/08 06:43 [medline]
PHST- 2024/01/08 04:50 [entrez]
PHST- 2024/01/05 00:00 [pmc-release]
AID - 2023.12.19.572439 [pii]
AID - 10.1101/2023.12.19.572439 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2023 Dec 19:2023.12.19.572439. doi: 
      10.1101/2023.12.19.572439.