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Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy

Ubiquitous deficiency in the survival motor neuron (SMN) protein causes death of motor neurons—a hallmark of the neurodegenerative disease spinal muscular atrophy (SMA)—through poorly understood mechanisms. Here, we show that the function of SMN in the assembly of spliceosomal small nuclear ribonucl...

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Autores principales: Van Alstyne, Meaghan, Simon, Christian M., Sardi, S. Pablo, Shihabuddin, Lamya S., Mentis, George Z., Pellizzoni, Livio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075148/
https://www.ncbi.nlm.nih.gov/pubmed/30012555
http://dx.doi.org/10.1101/gad.316059.118
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author Van Alstyne, Meaghan
Simon, Christian M.
Sardi, S. Pablo
Shihabuddin, Lamya S.
Mentis, George Z.
Pellizzoni, Livio
author_facet Van Alstyne, Meaghan
Simon, Christian M.
Sardi, S. Pablo
Shihabuddin, Lamya S.
Mentis, George Z.
Pellizzoni, Livio
author_sort Van Alstyne, Meaghan
collection PubMed
description Ubiquitous deficiency in the survival motor neuron (SMN) protein causes death of motor neurons—a hallmark of the neurodegenerative disease spinal muscular atrophy (SMA)—through poorly understood mechanisms. Here, we show that the function of SMN in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) regulates alternative splicing of Mdm2 and Mdm4, two nonredundant repressors of p53. Decreased inclusion of critical Mdm2 and Mdm4 exons is most prominent in SMA motor neurons and correlates with both snRNP reduction and p53 activation in vivo. Importantly, increased skipping of Mdm2 and Mdm4 exons regulated by SMN is necessary and sufficient to synergistically elicit robust p53 activation in wild-type mice. Conversely, restoration of full-length Mdm2 and Mdm4 suppresses p53 induction and motor neuron degeneration in SMA mice. These findings reveal that loss of SMN-dependent regulation of Mdm2 and Mdm4 alternative splicing underlies p53-mediated death of motor neurons in SMA, establishing a causal link between snRNP dysfunction and neurodegeneration.
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spelling pubmed-60751482019-02-01 Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy Van Alstyne, Meaghan Simon, Christian M. Sardi, S. Pablo Shihabuddin, Lamya S. Mentis, George Z. Pellizzoni, Livio Genes Dev Research Paper Ubiquitous deficiency in the survival motor neuron (SMN) protein causes death of motor neurons—a hallmark of the neurodegenerative disease spinal muscular atrophy (SMA)—through poorly understood mechanisms. Here, we show that the function of SMN in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) regulates alternative splicing of Mdm2 and Mdm4, two nonredundant repressors of p53. Decreased inclusion of critical Mdm2 and Mdm4 exons is most prominent in SMA motor neurons and correlates with both snRNP reduction and p53 activation in vivo. Importantly, increased skipping of Mdm2 and Mdm4 exons regulated by SMN is necessary and sufficient to synergistically elicit robust p53 activation in wild-type mice. Conversely, restoration of full-length Mdm2 and Mdm4 suppresses p53 induction and motor neuron degeneration in SMA mice. These findings reveal that loss of SMN-dependent regulation of Mdm2 and Mdm4 alternative splicing underlies p53-mediated death of motor neurons in SMA, establishing a causal link between snRNP dysfunction and neurodegeneration. Cold Spring Harbor Laboratory Press 2018-08-01 /pmc/articles/PMC6075148/ /pubmed/30012555 http://dx.doi.org/10.1101/gad.316059.118 Text en © 2018 Van Alstyne et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Van Alstyne, Meaghan
Simon, Christian M.
Sardi, S. Pablo
Shihabuddin, Lamya S.
Mentis, George Z.
Pellizzoni, Livio
Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy
title Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy
title_full Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy
title_fullStr Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy
title_full_unstemmed Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy
title_short Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy
title_sort dysregulation of mdm2 and mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075148/
https://www.ncbi.nlm.nih.gov/pubmed/30012555
http://dx.doi.org/10.1101/gad.316059.118
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