ASO targeting RBM3 temperature-controlled poison exon splicing prevents neurodegeneration in vivo.
RBM3
alternative splicing coupled to nonsense-mediated decay
hypothermia
neurodegenerative diseases
neuroprotection
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
08 05 2023
08 05 2023
Historique:
revised:
16
02
2023
received:
09
11
2022
accepted:
18
02
2023
medline:
9
5
2023
pubmed:
23
3
2023
entrez:
22
3
2023
Statut:
ppublish
Résumé
Neurodegenerative diseases are increasingly prevalent in the aging population, yet no disease-modifying treatments are currently available. Increasing the expression of the cold-shock protein RBM3 through therapeutic hypothermia is remarkably neuroprotective. However, systemic cooling poses a health risk, strongly limiting its clinical application. Selective upregulation of RBM3 at normothermia thus holds immense therapeutic potential. Here we identify a poison exon within the RBM3 gene that is solely responsible for its cold-induced expression. Genetic removal or antisense oligonucleotide (ASO)-mediated manipulation of this exon yields high RBM3 levels independent of cooling. Notably, a single administration of ASO to exclude the poison exon, using FDA-approved chemistry, results in long-lasting increased RBM3 expression in mouse brains. In prion-diseased mice, this treatment leads to remarkable neuroprotection, with prevention of neuronal loss and spongiosis despite high levels of disease-associated prion protein. Our promising results in mice support the possibility that RBM3-inducing ASOs might also deliver neuroprotection in humans in conditions ranging from acute brain injury to Alzheimer's disease.
Identifiants
pubmed: 36946385
doi: 10.15252/emmm.202217157
pmc: PMC10165353
doi:
Substances chimiques
Oligonucleotides, Antisense
0
Poisons
0
RNA-Binding Proteins
0
RBM3 protein, human
0
Rbm3 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e17157Subventions
Organisme : Medical Research Council
ID : MC_U132692719
Pays : United Kingdom
Informations de copyright
© 2023 The Authors. Published under the terms of the CC BY 4.0 license.
Références
Science. 2012 Oct 19;338(6105):379-83
pubmed: 22923437
Nat Med. 2021 Mar;27(3):536-545
pubmed: 33707773
RNA. 2017 Feb;23(2):189-201
pubmed: 27864472
Mol Cell. 2020 Apr 2;78(1):57-69.e4
pubmed: 32059760
PLoS Comput Biol. 2018 Aug 17;14(8):e1006360
pubmed: 30118475
Sci Transl Med. 2011 Mar 2;3(72):72ra18
pubmed: 21368223
Nature. 2011 Oct 05;478(7367):123-6
pubmed: 21979052
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Nucleic Acids Res. 2022 Jul 8;50(12):6769-6785
pubmed: 35713540
Nat Commun. 2019 Sep 4;10(1):3983
pubmed: 31484925
Nat Protoc. 2012 Sep;7(9):1741-54
pubmed: 22936216
J Cell Mol Med. 2019 Oct;23(10):7010-7020
pubmed: 31436914
Nat Rev Drug Discov. 2021 Jun;20(6):412-413
pubmed: 34012000
EMBO Rep. 2020 Dec 3;21(12):e51369
pubmed: 33140569
Nature. 2015 Feb 12;518(7538):236-9
pubmed: 25607368
Science. 2003 Oct 31;302(5646):871-4
pubmed: 14593181
N Engl J Med. 2013 Dec 5;369(23):2197-206
pubmed: 24237006
N Engl J Med. 2005 Oct 13;353(15):1574-84
pubmed: 16221780
Neuron. 2007 Feb 1;53(3):325-35
pubmed: 17270731
Nature. 2012 May 06;485(7399):507-11
pubmed: 22622579
J Clin Med. 2022 Feb 11;11(4):
pubmed: 35207221
Biochem Biophys Res Commun. 1997 Jul 30;236(3):804-7
pubmed: 9245737
Lancet. 2017 Dec 17;388(10063):3017-3026
pubmed: 27939059
Mol Cell. 2017 Aug 3;67(3):433-446.e4
pubmed: 28689656
Mol Cell. 2014 May 22;54(4):651-62
pubmed: 24837677
Curr Biol. 2017 Mar 6;27(5):638-650
pubmed: 28238655
EMBO J. 2002 Feb 1;21(3):202-10
pubmed: 11823413
Lancet Glob Health. 2021 Sep;9(9):e1273-e1285
pubmed: 34358491
N Engl J Med. 2019 Dec 12;381(24):2327-2337
pubmed: 31577396
Physiol Plant. 2015 Jan;153(1):1-11
pubmed: 25243592
PLoS One. 2019 Dec 10;14(12):e0226005
pubmed: 31821351
Neuroscience. 2015 Oct 1;305:268-78
pubmed: 26265550
Circulation. 2016 Sep 13;134(11):797-805
pubmed: 27562972
J Cell Biol. 2015 May 11;209(3):419-33
pubmed: 25963821
Nat Commun. 2020 Jul 9;11(1):3501
pubmed: 32647108
N Engl J Med. 2021 Jun 17;384(24):2283-2294
pubmed: 34133859
N Engl J Med. 2014 Jul 10;371(2):140-9
pubmed: 25006720
Nat Med. 2021 Mar;27(3):526-535
pubmed: 33707772
Sci Rep. 2013;3:2054
pubmed: 23792593
Wiley Interdiscip Rev RNA. 2018 Mar;9(2):
pubmed: 29322631
N Engl J Med. 2002 Feb 21;346(8):549-56
pubmed: 11856793
Elife. 2019 Feb 05;8:
pubmed: 30720431
Neurobiol Dis. 2011 Aug;43(2):388-96
pubmed: 21527344
Nat Med. 2013 Nov;19(11):1489-1495
pubmed: 24097189
Nat Rev Mol Cell Biol. 2015 Nov;16(11):665-77
pubmed: 26397022
Annu Rev Neurosci. 2019 Jul 8;42:385-406
pubmed: 31283897
Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10238-43
pubmed: 18632556
Nat Protoc. 2013 Nov;8(11):2281-2308
pubmed: 24157548
Life Sci Alliance. 2021 Feb 9;4(4):
pubmed: 33563652
EMBO Mol Med. 2023 May 8;15(5):e17157
pubmed: 36946385
N Engl J Med. 2022 Sep 22;387(12):1099-1110
pubmed: 36129998
Nucleic Acids Res. 2020 Apr 6;48(6):2853-2865
pubmed: 32103257
Clin Perinatol. 2012 Dec;39(4):919-29
pubmed: 23164187
J Cell Biol. 1997 May 19;137(4):899-908
pubmed: 9151692
Oncotarget. 2017 Mar 28;8(13):22235-22250
pubmed: 28118608