SMN controls neuromuscular junction integrity through U7 snRNP

Tisdale, Sarah; Alstyne, Meaghan Van; Simon, Christian M.; Mentis, George Z.; Pellizzoni, Livio

doi:10.1016/j.celrep.2022.111393

Cited by 12 publications

(8 citation statements)

References 71 publications

(179 reference statements)

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“…Clearly, the assembly of U7 snRNP must be under strict cellular surveillance to prevent binding of the highly abundant SmD1/D2 heterodimer to U7 snRNA, yielding dysfunctional and potentially harmful complexes. Previous in vitro and in vivo studies established that the assembly of the U7-specific Sm ring on U7 snRNA utilizes at least some components of the PRMT5 and SMN complexes but how exactly they work together to achieve this goal and to distinguish U7 snRNP from the spliceosomal snRNPs is unknown (Schumperli and Pillai 2004;Tisdale et al 2013;Tisdale et al 2022). Here, we took a closer look at the role of the PRMT5 methylosome in this process.…”

Section: Discussionmentioning

confidence: 99%

“…Initial studies on U7 snRNP suggested that its assembly is at least partially similar to the assembly of the spliceosomal snRNPs, involving both the PRMT5 and SMN proteins ( Pillai et al 2003 ; Schumperli and Pillai 2004 ; Azzouz et al 2005 ; Li et al 2014 ). More recent studies supported this conclusion by showing that pICln recruits the Lsm10/11 heterodimer to the PRMT5/MEP50 heterooctamer ( Paknia et al 2016 ), and that down-regulation of the SMN protein impairs the assembly of U7 snRNP, resulting in a defect in 3′ end processing of histone pre-mRNAs ( Tisdale et al 2013 , 2022 ). However, an open question was whether Lsm10 and/or Lsm11 become symmetrically dimethylated by PRMT5, or the interaction of the Lsm10/11 heterodimer with the methylosome plays other than catalytic role(s) in U7 snRNP assembly, contrasting with the assembly of the spliceosomal snRNPs ( Azzouz et al 2005 ).…”

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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In vitro methylation of the U7 snRNP subunits Lsm11 and SmE by the PRMT5/MEP50/pICln methylosome

Yang

Desotell

Lin

et al. 2023

RNA

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U7 snRNP is a multi-subunit endonuclease required for 3’ end processing of metazoan replication-dependent histone pre-mRNAs. In contrast to the spliceosomal snRNPs, U7 snRNP lacks the Sm subunits D1 and D2 and instead contains two related proteins, Lsm10 and Lsm11. The remaining five subunits of the U7 heptameric Sm ring, SmE, F, G, B and D3, are shared with the spliceosomal snRNPs. The pathway that assembles the unique ring of U7 snRNP is unknown. Here, we show that a heterodimer of Lsm10 and Lsm11 tightly interacts with the methylosome, a complex of the arginine methyltransferase PRMT5, MEP50 and pICln known to methylate arginines in the C-terminal regions of the Sm proteins B, D1 and D3 during the spliceosomal Sm ring assembly. Both biochemical and Cryo-EM structural studies demonstrate that the interaction is mediated by PRMT5, which binds and methylates two arginine residues in the N-terminal region of Lsm11. Surprisingly, PRMT5 also methylates an N-terminal arginine in SmE, a subunit that does not undergo this type of modification during the biogenesis of the spliceosomal snRNPs. An intriguing possibility is that the unique methylation pattern of Lsm11 and SmE plays a vital role in the assembly of the U7 snRNP.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

In vitro methylation of the U7 snRNP subunits Lsm11 and SmE by the PRMT5/MEP50/pICln methylosome

Yang

Desotell

Lin

et al. 2023

RNA

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“…Defective local translation [ 19 ] and disruption of cytoskeleton and ubiquitin homeostasis [ 22 ] are likely to induce the devastating alterations observed at the neuromuscular junction (NMJ), an early pathogenic marker of SMA [ 120 , 121 ]. Here, numerous defects in mRNA transport, translation, and proteostasis of pivotal proteins for NMJ maturation and functional maintenance have been reported [ 2 , 22 , 79 , 122 ].…”

Section: Direct and Indirect Translational Defects In Smamentioning

confidence: 99%

The SMN-ribosome interplay: a new opportunity for Spinal Muscular Atrophy therapies

Sharma,

Paganin,

Lauria

et al. 2024

Biochemical Society Transactions

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The underlying cause of Spinal Muscular Atrophy (SMA) is in the reduction of survival motor neuron (SMN) protein levels due to mutations in the SMN1 gene. The specific effects of SMN protein loss and the resulting pathological alterations are not fully understood. Given the crucial roles of the SMN protein in snRNP biogenesis and its interactions with ribosomes and translation-related proteins and mRNAs, a decrease in SMN levels below a specific threshold in SMA is expected to affect translational control of gene expression. This review covers both direct and indirect SMN interactions across various translation-related cellular compartments and processes, spanning from ribosome biogenesis to local translation and beyond. Additionally, it aims to outline deficiencies and alterations in translation observed in SMA models and patients, while also discussing the implications of the relationship between SMN protein and the translation machinery within the context of current and future therapies.

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“…The role of agrin/LRP4/MuSK/Dok7 signalling pathway in SMA disease was first underlined by the observation that agrin Z + exon is mis-spliced in spinal motoneurons of SMA model mice 37 , that can be corrected by the co-expression of AAV-9 U7-specific Lsm10 and Lsm11 proteins 38 . Modulation of agrin signalling by either the overexpression of a transgenic Z + agrin, injection of a therapeutic agrin or AAV-Dok7 delivery mitigates the phenotype of SMA mice 39 – 41 .…”

Section: Introductionmentioning

confidence: 99%

A link between agrin signalling and Cav3.2 at the neuromuscular junction in spinal muscular atrophy

Delers

Sapaly

Salman

et al. 2022

Sci Rep

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SMN protein deficiency causes motoneuron disease spinal muscular atrophy (SMA). SMN-based therapies improve patient motor symptoms to variable degrees. An early hallmark of SMA is the perturbation of the neuromuscular junction (NMJ), a synapse between a motoneuron and muscle cell. NMJ formation depends on acetylcholine receptor (AChR) clustering triggered by agrin and its co-receptors lipoprotein receptor-related protein 4 (LRP4) and transmembrane muscle-specific kinase (MuSK) signalling pathway. We have previously shown that flunarizine improves NMJs in SMA model mice, but the mechanisms remain elusive. We show here that flunarizine promotes AChR clustering in cell-autonomous, dose- and agrin-dependent manners in C2C12 myotubes. This is associated with an increase in protein levels of LRP4, integrin-beta-1 and alpha-dystroglycan, three agrin co-receptors. Furthermore, flunarizine enhances MuSK interaction with integrin-beta-1 and phosphotyrosines. Moreover, the drug acts on the expression and splicing of Agrn and Cacna1h genes in a muscle-specific manner. We reveal that the Cacna1h encoded protein Cav3.2 closely associates in vitro with the agrin co-receptor LRP4. In vivo, it is enriched nearby NMJs during neonatal development and the drug increases this immunolabelling in SMA muscles. Thus, flunarizine modulates key players of the NMJ and identifies Cav3.2 as a new protein involved in the NMJ biology.

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SMN controls neuromuscular junction integrity through U7 snRNP

Cited by 12 publications

References 71 publications

In vitro methylation of the U7 snRNP subunits Lsm11 and SmE by the PRMT5/MEP50/pICln methylosome

In vitro methylation of the U7 snRNP subunits Lsm11 and SmE by the PRMT5/MEP50/pICln methylosome

The SMN-ribosome interplay: a new opportunity for Spinal Muscular Atrophy therapies

A link between agrin signalling and Cav3.2 at the neuromuscular junction in spinal muscular atrophy

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