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

Alstyne, Meaghan Van; Simon, Christian M.; Sardi, S. Pablo; Shihabuddin, Lamya S.; Mentis, George Z.; Pellizzoni, Livio

doi:10.1101/gad.316059.118

Cited by 59 publications

(165 citation statements)

References 55 publications

(126 reference statements)

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“…We also showed that selectivity is established through the convergence of distinct mechanisms of p53 regulation including stabilization and phosphorylation of its N-terminal transcription-activation domain (TAD) , which only occur in the pool of vulnerable SMA motor neurons destined to die. Recently, we demonstrated that p53 upregulation results from dysregulated alternative splicing of Mdm2 and Mdm4 -the two main inhibitors of p53's stability and function (Toledo and Wahl, 2006;Vousden and Prives, 2009) -due to reduced snRNP levels in SMA motor neurons (Van Alstyne et al, 2018a), thereby directly linking neurodegeneration to specific splicing changes induced by SMN deficiency. However, the converging mechanism(s) responsible for selective phosphorylation of the TAD of p53 required for degeneration of SMA motor neurons is unknown.…”

Section: Introductionmentioning

confidence: 99%

Stasimon contributes to the loss of sensory synapses and motor neuron death in a mouse model of spinal muscular atrophy

Simon

Alstyne

Lotti

et al. 2019

Preprint

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Reduced expression of the SMN protein causes spinal muscular atrophy (SMA) -an inherited neurodegenerative disease characterized by multiple synaptic deficits and motor neuron loss. Here, we show that AAV9-mediated delivery of Stasimon -a gene encoding an ER-resident transmembrane protein regulated by SMN -improves motor function in a mouse model of SMA through multiple mechanisms. In proprioceptive neurons of SMA mice, Stasimon overexpression prevents the loss of afferent synapses on motor neurons and enhances sensory-motor neurotransmission. In SMA motor neurons, Stasimon suppresses the neurodegenerative process by selectively reducing phosphorylation but not upregulation of the tumor suppressor p53, both of which are converging events required to trigger neuronal death. We further show that Stasimon deficiency synergizes with SMA-related mechanisms of p53 upregulation to induce phosphorylation of p53. These findings identify Stasimon dysfunction induced by SMN deficiency as an upstream driver of cellular pathways that lead to synaptic loss and motor neuron degeneration, revealing a dual contribution of Stasimon to motor circuit pathology in SMA.

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Section: Introductionmentioning

confidence: 99%

Stasimon contributes to the loss of sensory synapses and motor neuron death in a mouse model of spinal muscular atrophy

Simon

Alstyne

Lotti

et al. 2019

Preprint

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“…p53 depletion rescues mdm2 mutant phenotypes (27). Abnormal mdm2 splicing and p53 activation are associated with the death of motor neurons in SMA (28). We found inhibition of the p53/Mdm2 pathway brought no alteration to survival or regeneration in the gemin5 mutants (Suppl.…”

Section: Discussionmentioning

confidence: 66%

“…9A). Several lines of published evidence indicate that p53 interacts with Mdm2 and activation of the p53/Mdm2 pathway is associated with SMN complex activity and SMA (27)(28)(29). To investigate a potential role for the tp53/Mdm2 pathway in hair cell regeneration, we depleted tp53 genetically in both the smn1 and gemin5 mutant backgrounds.…”

Section: Observed Upregulation Of the Tp53/mdm2 Pathway Was Not The Mmentioning

confidence: 99%

A subset of SMN complex members have a specific role in tissue regeneration via ERBB pathway-mediated proliferation

Pei

Chen

Slevin

et al. 2019

Preprint

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Spinal Muscular Atrophy (SMA) is the most common genetic disease in childhood. SMA is generally caused by mutations in SMN1. The Survival of Motor Neurons (SMN) complex consists of SMN1, Gemins (2-8) and Strap/Unrip. We previously demonstrated smn1 and gemin5 inhibited tissue regeneration in zebrafish. Here we investigated each individual SMN complex member and identified gemin3 as another regeneration-essential gene. These three genes are likely pan-regenerative since they affect the regeneration of hair cells, liver and caudal fin. RNA-Seq and miRNA-Seq analyses reveal that smn1, gemin3, and gemin5 are linked to a common set of genetic pathways, including the tp53 and ErbB pathways. Additional studies indicated all three genes facilitate regeneration by inhibiting the ErbB pathway, thereby allowing cell proliferation in the injured neuromasts. This study provides a new understanding of the SMN complex and a potential etiology for SMA and potentially other rare unidentified genetic diseases with similar symptoms.

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“…A second study suggests that the underlying mechanism of motor neuron death in SMA is related to p53 signaling, specifically altered splicing of two p53 repressors, Mdm2 and Mdm4 (Van Alstyne et al, ). Using an SMA mouse model, the authors demonstrate that SMN deficiency selectively promotes exon skipping of two major spliceosome regulated exons, Mdm2 Exon 3 and Mdm4 Exon 7.…”

Section: Spinal Muscular Atrophymentioning

confidence: 99%

Splicing and neurodegeneration: Insights and mechanisms

Nik

Bowman

2019

WIREs RNA

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Splicing is the global cellular process whereby intervening sequences (introns) in precursor messenger RNA (pre‐mRNA) are removed and expressed regions (exons) are ligated together, resulting in a mature mRNA transcript that is exported and translated in the cytoplasm. The tightly regulated splicing cycle is also flexible allowing for the inclusion or exclusion of some sequences depending on the specific cellular context. Alternative splicing allows for the generation of many transcripts from a single gene, thereby expanding the proteome. Although all cells require the function of the spliceosome, neurons are highly sensitive to splicing perturbations with numerous neurological diseases linked to splicing defects. The sensitivity of neurons to splicing alterations is largely due to the complex neuronal cell types and functions in the nervous system that require specific splice isoforms to maintain cellular homeostasis. In the past several years, the relationship between RNA splicing and the nervous system has been the source of significant investigation. Here, we review the current knowledge on RNA splicing in neurobiology and discuss its potential role and impact in neurodegenerative diseases. We will examine the impact of alternative splicing and the role of splicing regulatory proteins on neurodegeneration, highlighting novel animal models including mouse and zebrafish. We will also examine emerging technologies and therapeutic interventions that aim to “drug” the spliceosome. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Development

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

Cited by 59 publications

References 55 publications

Stasimon contributes to the loss of sensory synapses and motor neuron death in a mouse model of spinal muscular atrophy

Stasimon contributes to the loss of sensory synapses and motor neuron death in a mouse model of spinal muscular atrophy

A subset of SMN complex members have a specific role in tissue regeneration via ERBB pathway-mediated proliferation

Splicing and neurodegeneration: Insights and mechanisms

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