GEMINs: potential therapeutic targets for spinal muscular atrophy?

Borg, Rebecca; Cauchi, Ruben J.

doi:10.3389/fnins.2014.00325

Cited by 16 publications

(11 citation statements)

References 72 publications

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“…). This result indicates that in line with that reported for the known SMN complex members , Gaulos is an essential gene. To determine whether a requirement for adult viability is due to a function within the neuromuscular system, we decreased Gaulos mRNA levels in either muscle or neurons starting from the earliest stages of development.…”

Section: Resultssupporting

confidence: 90%

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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Section: Resultssupporting

confidence: 90%

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

et al. 2017

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“…Complete deletion of any component of the SMN-Gemins complex is incompatible with life whereas a perturbation that is restricted to the motor unit has a negative influence on motor function (reviewed in [ 59 ]). There is a plethora of evidence that links loss-of-function to defects in snRNP biogenesis with downstream consequences on splicing [ 29 , 31 – 34 , 60 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic Interactions between the Members of the SMN-Gemins Complex in Drosophila

et al. 2015

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The SMN-Gemins complex is composed of Gemins 2–8, Unrip and the survival motor neuron (SMN) protein. Limiting levels of SMN result in the neuromuscular disorder, spinal muscular atrophy (SMA), which is presently untreatable. The most-documented function of the SMN-Gemins complex concerns the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs). Despite multiple genetic studies, the Gemin proteins have not been identified as prominent modifiers of SMN-associated mutant phenotypes. In the present report, we make use of the Drosophila model organism to investigate whether viability and motor phenotypes associated with a hypomorphic Gemin3 mutant are enhanced by changes in the levels of SMN, Gemin2 and Gemin5 brought about by various genetic manipulations. We show a modifier effect by all three members of the minimalistic fly SMN-Gemins complex within the muscle compartment of the motor unit. Interestingly, muscle-specific overexpression of Gemin2 was by itself sufficient to depress normal motor function and its enhanced upregulation in all tissues leads to a decline in fly viability. The toxicity associated with increased Gemin2 levels is conserved in the yeast S. pombe in which we find that the cytoplasmic retention of Sm proteins, likely reflecting a block in the snRNP assembly pathway, is a contributing factor. We propose that a disruption in the normal stoichiometry of the SMN-Gemins complex depresses its function with consequences that are detrimental to the motor system.

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“…It is possible that the current SMNdependent therapies of SMA might not cause sufficient long-term phenotype improvements for all patients (Singh, 2019) and might also require increasing the functions of the components of the SMN-Gemins complex. Pharmacological approaches to augment the protein levels of the Gemins may therefore be justified in combination with the recently approved SMA therapies that upregulate SMN protein levels (Borg and Cauchi, 2014). Thus, we expect that a more detailed understanding of the molecular mechanisms of SMA disease should benefit to the development of the future therapies against motor neuron diseases.…”

Section: Discussionmentioning

confidence: 99%

The Small-Molecule Flunarizine in Spinal Muscular Atrophy Patient Fibroblasts Impacts on the Gemin Components of the SMN Complex and TDP43, an RNA-Binding Protein Relevant to Motor Neuron Diseases

Sapaly

Delers

Coridon

et al. 2020

Front. Mol. Biosci.

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GEMINs: potential therapeutic targets for spinal muscular atrophy?

Cited by 16 publications

References 72 publications

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

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

Genetic Interactions between the Members of the SMN-Gemins Complex in Drosophila

The Small-Molecule Flunarizine in Spinal Muscular Atrophy Patient Fibroblasts Impacts on the Gemin Components of the SMN Complex and TDP43, an RNA-Binding Protein Relevant to Motor Neuron Diseases

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