Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy
- Meaghan Van Alstyne1,2,
- Christian M. Simon1,2,5,
- S. Pablo Sardi3,
- Lamya S. Shihabuddin3,
- George Z. Mentis1,2,4 and
- Livio Pellizzoni1,2
- 1Center for Motor Neuron Biology and Disease, Columbia University, New York, New York 10032, USA;
- 2Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA;
- 3Neuroscience Therapeutic Area, Sanofi, Framingham, Massachusetts 01701, USA;
- 4Department of Neurology, Columbia University, New York, New York 10032, USA
- Corresponding author: lp2284{at}cumc.columbia.edu
Abstract
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.
Keywords
- spinal muscular atrophy (SMA)
- survival motor neuron (SMN)
- small nuclear ribonucleoprotein (snRNP)
- p53
- Mdm2
- Mdm4
Footnotes
-
Supplemental material is available for this article.
-
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.316059.118.
- Received April 26, 2018.
- Accepted May 24, 2018.
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/.