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Genes Dev. 2018 Aug 1;32(15-16):1045-1059. doi: 10.1101/gad.316059.118. Epub 2018 Jul 16.

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

Author information

1
Center for Motor Neuron Biology and Disease, Columbia University, New York, New York 10032, USA.
2
Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
3
Neuroscience Therapeutic Area, Sanofi, Framingham, Massachusetts 01701, USA.
4
Department of Neurology, Columbia University, New York, New York 10032, USA.

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:

Mdm2; Mdm4; p53; small nuclear ribonucleoprotein (snRNP); spinal muscular atrophy (SMA); survival motor neuron (SMN)

PMID:
30012555
PMCID:
PMC6075148
DOI:
10.1101/gad.316059.118
[Indexed for MEDLINE]
Free PMC Article

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