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Changes in intranuclear mobility of mature snRNPs provide a mechanism for splicing defects in spinal muscular atrophy
It is becoming increasingly clear that defects in RNA metabolism can lead to disease. Spinal muscular atrophy (SMA), a leading genetic cause of infant mortality, results from insufficient amounts of survival motor neuron (SMN) protein. SMN is required for the biogenesis of small nuclear ribonucleopr...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Company of Biologists
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3403233/ https://www.ncbi.nlm.nih.gov/pubmed/22393244 http://dx.doi.org/10.1242/jcs.096867 |
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author | Clelland, Allyson Kara Bales, Alexandra Beatrice E. Sleeman, Judith Elizabeth |
author_facet | Clelland, Allyson Kara Bales, Alexandra Beatrice E. Sleeman, Judith Elizabeth |
author_sort | Clelland, Allyson Kara |
collection | PubMed |
description | It is becoming increasingly clear that defects in RNA metabolism can lead to disease. Spinal muscular atrophy (SMA), a leading genetic cause of infant mortality, results from insufficient amounts of survival motor neuron (SMN) protein. SMN is required for the biogenesis of small nuclear ribonucleoproteins (snRNPs): essential components of the spliceosome. Splicing abnormalities have been detected in models of SMA but it is unclear how lowered SMN affects the fidelity of pre-mRNA splicing. We have examined the dynamics of mature snRNPs in cells depleted of SMN and demonstrated that SMN depletion increases the mobility of mature snRNPs within the nucleus. To dissect the molecular mechanism by which SMN deficiency affects intranuclear snRNP mobility, we employed a panel of inhibitors of different stages of pre-mRNA processing. This in vivo modelling demonstrates that snRNP mobility is altered directly as a result of impaired snRNP maturation. Current models of nuclear dynamics predict that subnuclear structures, including the spliceosome, form by self-organization mediated by stochastic interactions between their molecular components. Thus, alteration of the intranuclear mobility of snRNPs provides a molecular mechanism for splicing defects in SMA. |
format | Online Article Text |
id | pubmed-3403233 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Company of Biologists |
record_format | MEDLINE/PubMed |
spelling | pubmed-34032332012-08-16 Changes in intranuclear mobility of mature snRNPs provide a mechanism for splicing defects in spinal muscular atrophy Clelland, Allyson Kara Bales, Alexandra Beatrice E. Sleeman, Judith Elizabeth J Cell Sci Research Articles It is becoming increasingly clear that defects in RNA metabolism can lead to disease. Spinal muscular atrophy (SMA), a leading genetic cause of infant mortality, results from insufficient amounts of survival motor neuron (SMN) protein. SMN is required for the biogenesis of small nuclear ribonucleoproteins (snRNPs): essential components of the spliceosome. Splicing abnormalities have been detected in models of SMA but it is unclear how lowered SMN affects the fidelity of pre-mRNA splicing. We have examined the dynamics of mature snRNPs in cells depleted of SMN and demonstrated that SMN depletion increases the mobility of mature snRNPs within the nucleus. To dissect the molecular mechanism by which SMN deficiency affects intranuclear snRNP mobility, we employed a panel of inhibitors of different stages of pre-mRNA processing. This in vivo modelling demonstrates that snRNP mobility is altered directly as a result of impaired snRNP maturation. Current models of nuclear dynamics predict that subnuclear structures, including the spliceosome, form by self-organization mediated by stochastic interactions between their molecular components. Thus, alteration of the intranuclear mobility of snRNPs provides a molecular mechanism for splicing defects in SMA. Company of Biologists 2012-06-01 /pmc/articles/PMC3403233/ /pubmed/22393244 http://dx.doi.org/10.1242/jcs.096867 Text en © 2012. http://creativecommons.org/licenses/by-nc-sa/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0/), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms. |
spellingShingle | Research Articles Clelland, Allyson Kara Bales, Alexandra Beatrice E. Sleeman, Judith Elizabeth Changes in intranuclear mobility of mature snRNPs provide a mechanism for splicing defects in spinal muscular atrophy |
title | Changes in intranuclear mobility of mature snRNPs provide a mechanism for splicing defects in spinal muscular atrophy |
title_full | Changes in intranuclear mobility of mature snRNPs provide a mechanism for splicing defects in spinal muscular atrophy |
title_fullStr | Changes in intranuclear mobility of mature snRNPs provide a mechanism for splicing defects in spinal muscular atrophy |
title_full_unstemmed | Changes in intranuclear mobility of mature snRNPs provide a mechanism for splicing defects in spinal muscular atrophy |
title_short | Changes in intranuclear mobility of mature snRNPs provide a mechanism for splicing defects in spinal muscular atrophy |
title_sort | changes in intranuclear mobility of mature snrnps provide a mechanism for splicing defects in spinal muscular atrophy |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3403233/ https://www.ncbi.nlm.nih.gov/pubmed/22393244 http://dx.doi.org/10.1242/jcs.096867 |
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