دورية أكاديمية
SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis.
| العنوان: | SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis. |
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| المؤلفون: | Castelli, Lydia M, Cutillo, Luisa, Souza, Cleide Dos Santos, Sanchez-Martinez, Alvaro, Granata, Ilaria, Lin, Ya-Hui, Myszczynska, Monika A, Heath, Paul R, Livesey, Matthew R, Ning, Ke, Azzouz, Mimoun, Shaw, Pamela J, Guarracino, Mario R, Whitworth, Alexander J, Ferraiuolo, Laura, Milo, Marta, Hautbergue, Guillaume M |
| بيانات النشر: | BioMed Central //dx.doi.org/10.1186/s13024-021-00475-y Molecular Neurodegeneration |
| سنة النشر: | 2021 |
| المجموعة: | Apollo - University of Cambridge Repository |
| مصطلحات موضوعية: | Amyotrophic lateral sclerosis, C9ORF72-repeat expansions, Disease-modifying gene expression signature, Genome-wide mechanisms of neuroprotection, Pre-clinical models, SRSF1-dependent RNA nuclear export, Transcriptome, Voltage-gated potassium ion channel |
| الوصف: | BACKGROUND: Loss of motor neurons in amyotrophic lateral sclerosis (ALS) leads to progressive paralysis and death. Dysregulation of thousands of RNA molecules with roles in multiple cellular pathways hinders the identification of ALS-causing alterations over downstream changes secondary to the neurodegenerative process. How many and which of these pathological gene expression changes require therapeutic normalisation remains a fundamental question. METHODS: Here, we investigated genome-wide RNA changes in C9ORF72-ALS patient-derived neurons and Drosophila, as well as upon neuroprotection taking advantage of our gene therapy approach which specifically inhibits the SRSF1-dependent nuclear export of pathological C9ORF72-repeat transcripts. This is a critical study to evaluate (i) the overall safety and efficacy of the partial depletion of SRSF1, a member of a protein family involved itself in gene expression, and (ii) a unique opportunity to identify neuroprotective RNA changes. RESULTS: Our study shows that manipulation of 362 transcripts out of 2257 pathological changes, in addition to inhibiting the nuclear export of repeat transcripts, is sufficient to confer neuroprotection in C9ORF72-ALS patient-derived neurons. In particular, expression of 90 disease-altered transcripts is fully reverted upon neuroprotection leading to the characterisation of a human C9ORF72-ALS disease-modifying gene expression signature. These findings were further investigated in vivo in diseased and neuroprotected Drosophila transcriptomes, highlighting a list of 21 neuroprotective changes conserved with 16 human orthologues in patient-derived neurons. We also functionally validated the high neuroprotective potential of one of these disease-modifying transcripts, demonstrating that inhibition of ALS-upregulated human KCNN1-3 (Drosophila SK) voltage-gated potassium channel orthologs mitigates degeneration of human motor neurons and Drosophila motor deficits. CONCLUSIONS: Strikingly, the partial depletion of SRSF1 leads to expression ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | https://www.repository.cam.ac.uk/handle/1810/329251Test |
| DOI: | 10.17863/CAM.76701 |
| الإتاحة: | https://doi.org/10.17863/CAM.76701Test https://www.repository.cam.ac.uk/handle/1810/329251Test |
| حقوق: | Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: | edsbas.D505B53E |
| قاعدة البيانات: | BASE |
| DOI: | 10.17863/CAM.76701 |
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