ASO targeting RBM3 temperature-controlled poison exon splicing prevents neurodegeneration in vivo
Autor: | Preußner, Marco, Smith, Heather L, Hughes, Daniel, Zhang, Min, Emmerichs, Ann-Kathrin, Scalzitti, Silvia, Peretti, Diego, Swinden, Dean, Neumann, Alexander, Haltenhof, Tom, Mallucci, Giovanna R, Heyd, Florian |
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Přispěvatelé: | Preußner, Marco [0000-0001-5155-0844], Hughes, Daniel [0000-0002-9706-5163], Mallucci, Giovanna R [0000-0001-8504-1191], Heyd, Florian [0000-0001-9377-9882], Apollo - University of Cambridge Repository |
Rok vydání: | 2023 |
Předmět: |
RBM3
Temperature RNA-Binding Proteins Oligonucleotides Antisense 600 Technik Medizin angewandte Wissenschaften::610 Medizin und Gesundheit::616 Krankheiten Poisons Cold Temperature alternative splicing coupled to nonsense-mediated decay Mice Humans Animals neurodegenerative diseases neuroprotection hypothermia Aged |
DOI: | 10.17863/cam.95240 |
Popis: | Funder: Freie Universität Berlin; Id: http://dx.doi.org/10.13039/501100007537 Funder: Cambridge Centre for Parkinson's Plus 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. |
Databáze: | OpenAIRE |
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