Disruption of snRNP biogenesis factors Tgs1 and pICln induces phenotypes that mirror aspects of SMN-Gemins complex perturbation in Drosophila, providing new insights into spinal muscular atrophy

Borg, Rebecca; Fenech-Salerno, Benji; Vassallo, Neville; Bordonne, Rémy; Cauchi, Ruben J.

doi:10.1016/j.nbd.2016.06.015

Cited by 19 publications

(40 citation statements)

References 76 publications

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“…This study is in agreement with an earlier report demonstrating that motor neuron degeneration was rescued when purified snRNPs were injected in SMN-deficient zebrafish embryos (Winkler et al, 2005). Interestingly, in line with earlier findings demonstrating that knockdown of pICln or U1 snRNP leads to SMA-like defects in zebrafish (Winkler et al, 2005; Yu et al, 2015) (Table 1), disruption of either pICln or Tgs1 was found to result in motor defects that mirror those described on loss of SMN or Gemins in Drosophila (Borg et al, 2016). pICln and Tgs1 are two factors that are known to have a leading role in the early and late phase of snRNP assembly, respectively.…”

Section: In Vivo Studies Linking Snrnp Assembly Defects To Neuromuscusupporting

confidence: 83%

Spinal Muscular Atrophy: From Defective Chaperoning of snRNP Assembly to Neuromuscular Dysfunction

Lanfranco

Vassallo

Cauchi

2017

Front. Mol. Biosci.

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Spinal Muscular Atrophy (SMA) is a neuromuscular disorder that results from decreased levels of the survival motor neuron (SMN) protein. SMN is part of a multiprotein complex that also includes Gemins 2–8 and Unrip. The SMN-Gemins complex cooperates with the protein arginine methyltransferase 5 (PRMT5) complex, whose constituents include WD45, PRMT5 and pICln. Both complexes function as molecular chaperones, interacting with and assisting in the assembly of an Sm protein core onto small nuclear RNAs (snRNAs) to generate small nuclear ribonucleoproteins (snRNPs), which are the operating components of the spliceosome. Molecular and structural studies have refined our knowledge of the key events taking place within the crowded environment of cells and the numerous precautions undertaken to ensure the faithful assembly of snRNPs. Nonetheless, it remains unclear whether a loss of chaperoning in snRNP assembly, considered as a “housekeeping” activity, is responsible for the selective neuromuscular phenotype in SMA. This review thus shines light on in vivo studies that point toward disturbances in snRNP assembly and the consequential transcriptome abnormalities as the primary drivers of the progressive neuromuscular degeneration underpinning the disease. Disruption of U1 snRNP or snRNP assembly factors other than SMN induces phenotypes that mirror aspects of SMN deficiency, and splicing defects, described in numerous SMA models, can lead to a DNA damage and stress response that compromises the survival of the motor system. Restoring the correct chaperoning of snRNP assembly is therefore predicted to enhance the benefit of SMA therapeutic modalities based on augmenting SMN expression.

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Section: In Vivo Studies Linking Snrnp Assembly Defects To Neuromuscusupporting

confidence: 83%

Spinal Muscular Atrophy: From Defective Chaperoning of snRNP Assembly to Neuromuscular Dysfunction

Lanfranco

Vassallo

Cauchi

2017

Front. Mol. Biosci.

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“…Our prediction is strengthened by secondary structure conservation in addition to their role in neuromuscular survival and function. We also show that the recently characterised Drosophila Unrip orthologue, wmd , can be recruited to the SMN complex via Sabbat, a possible orthologue of Gemin7. The identification of Hezron, the most likely orthologue of Gemin6, which latches to the SMN complex via Sabbat/Gemin7 completes the search for the discovery of the Gemin orthologues in Drosophila .…”

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confidence: 57%

“…Drosophila remains an attractive model system to investigate the in vivo function of human orthologues . Making use of this model, we and others have previously shown that loss of SMN, Gemin2, Gemin3, Gemin5, and Unrip leads to neuromuscular dysfunction . Importantly, components of the Drosophila SMN complex were shown to interact genetically in addition to physically .…”

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confidence: 99%

“…Hence, in contrast to the elaborate ninemembered version in vertebrates, including humans, in its simplest form found in the fission yeast Schizosaccharomyces pombe and the parasitic protozoan Trypanosoma brucei, the SMN complex is composed of only SMN and Gemin2 [11][12][13]. A slightly larger SMN complex comprising SMN, Gemin2, Gemin3, Gemin5, and, possibly, Unrip amongst its constituents is present in the fruit fly Drosophila melanogaster [14][15][16]. Interestingly, orthologues of most of the remaining Gemins appear to be absent in Drosophila although they are present in closely related species including the honey bee Apis mellifera and the parasitic wasp Nasonia vitripennis [11].…”

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confidence: 99%

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Novel interactors of the Drosophila Survival Motor Neuron (SMN) Complex suggest its full conservation

et al. 2017

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The Spinal Muscular Atrophy disease protein Survival Motor Neuron (SMN) operates as part of a multiprotein complex whose components also include Gemins 2-8 and Unrip. The fruit fly Drosophila melanogaster is thought to have a slightly smaller SMN complex comprised of SMN, Gemin2/3/5 and, possibly, Unrip. Based upon in vivo interaction methods, we have identified novel interacting partners of the Drosophila SMN complex with homologies to Gemin4/6/7/8. The Gemin4 and Gemin8 orthologues are required for neuromuscular function and survival. The Gemin6/7/Unrip module can be recruited via the SMN-associated Gemin8, hence mirroring the human SMN complex architecture. Our findings lead us to propose that an elaborate SMN complex that is typical in metazoans is also present in Drosophila.

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“…At this stage, the pre-snRNA also undergoes the 3′ end trimming [132]. A direct interaction between SMN and TGS1 appears to be essential for the formation of the TMG cap structure on pre-snRNAs [99,136]. Still bound to SMN complex, the newly processed snRNP is imported back into the nucleus.…”

Section: Role Of Smn In Rna Metabolismmentioning

confidence: 99%

Diverse role of survival motor neuron protein

Singh

Howell

Ottesen

et al. 2017

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

227

194

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The multifunctional Survival Motor Neuron (SMN) protein is required for the survival of all organisms of the animal kingdom. SMN impacts various aspects of RNA metabolism through the formation and/or interaction with ribonucleoprotein (RNP) complexes. SMN regulates biogenesis of small nuclear RNPs, small nucleolar RNPs, small Cajal body-associated RNPs, signal recognition particles and telomerase. SMN also plays an important role in DNA repair, transcription, pre-mRNA splicing, histone mRNA processing, translation, selenoprotein synthesis, macromolecular trafficking, stress granule formation, cell signaling and cytoskeleton maintenance. The tissue-specific requirement of SMN is dictated by the variety and the abundance of its interacting partners. Reduced expression of SMN causes spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA displays a broad spectrum ranging from embryonic lethality to an adult onset. Aberrant expression and/or localization of SMN has also been associated with male infertility, inclusion body myositis, amyotrophic lateral sclerosis and osteoarthritis. This review provides a summary of various SMN functions with implications to a better understanding of SMA and other pathological conditions.

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Disruption of snRNP biogenesis factors Tgs1 and pICln induces phenotypes that mirror aspects of SMN-Gemins complex perturbation in Drosophila, providing new insights into spinal muscular atrophy

Cited by 19 publications

References 76 publications

Spinal Muscular Atrophy: From Defective Chaperoning of snRNP Assembly to Neuromuscular Dysfunction

Spinal Muscular Atrophy: From Defective Chaperoning of snRNP Assembly to Neuromuscular Dysfunction

Novel interactors of the Drosophila Survival Motor Neuron (SMN) Complex suggest its full conservation

Diverse role of survival motor neuron protein

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