Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy

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

doi:10.2139/ssrn.3400853

Cited by 9 publications

(31 citation statements)

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“…Thus, loss of either protein leads to substantial transcriptome alterations. These alterations may be neurotoxic by directly affecting specific transcripts important for neuronal survival and function, a scenario supported by increasing experimental evidence (80)(81)(82)87). Importantly, we found that TGS1 overexpression can partially rescue the neurological phenotypes caused by SMN depletion.…”

Section: Discussionsupporting

confidence: 74%

“…This will likely require the development of SMN-independent strategies targeting diseaserelevant downstream pathways (88)(89)(90)(91)(92). Candidate targets have been emerging from studies in model organisms (63,69,81,82,93). Here, we have shown that TGS1 expression can compensate, at least in part, for SMN loss in animal models of neurodegeneration, suggesting that modulation of TGS1 activity may be a new potential therapeutic avenue for SMA.…”

Section: Discussionmentioning

confidence: 80%

“…studies in model organisms(63,69,81,82,93). Here, we have shown that TGS1 expression can compensate, at least in part, for SMN loss in animal models of neurodegeneration, suggesting that modulation of TGS1 activity may be a new potential therapeutic avenue for SMA.…”

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confidence: 75%

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TGS1 controls snRNA 3’ end processing, prevents neurodegeneration and ameliorates SMN-dependent neurological phenotypes in vivo

Chen

Roake

Maccallini

et al. 2020

Preprint

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Trimethylguanosine synthase 1 (TGS1) is a highly conserved enzyme that converts the 5' mono-methylguanosine cap of snRNAs to a trimethylguanosine cap. Here, we show that loss of TGS1 in C. elegans, D. melanogaster and D. rerio results in neurological phenotypes similar to those caused by Survival Motor Neuron (SMN) deficiency. Importantly, expression of human TGS1 ameliorates the SMN-dependent neurological phenotypes in both flies and worms, revealing that TGS1 has the ability to counteract the effects of SMN deficiency. TGS1 loss in HeLa cells leads to the accumulation of immature U2 and U4atac snRNAs with long 3' tails that are often uridylated. snRNAs with defective 3' terminations also accumulate in Drosophila Tgs1 mutants. Consistent with defective snRNA maturation, TGS1 and SMN mutant cells exhibit partially overlapping transcriptome alterations. Together, these results identify a neuroprotective function for TGS1, reinforcing the view that defects in snRNA maturation negatively affect neuronal viability and function.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 80%

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TGS1 controls snRNA 3’ end processing, prevents neurodegeneration and ameliorates SMN-dependent neurological phenotypes in vivo

Chen

Roake

Maccallini

et al. 2020

Preprint

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“…As mentioned earlier, molecular analysis of Drosophila Smn mutants led to the identification of Stasimon, an Smn target gene whose expression in neurons restores the neurological defects elicited by Smn mutations [20]. Stasimon orthologs share a conserved function and ameliorate the Smn loss of function phenotype also in zebrafish and mice [20,25]. Other modifiers of the Smn-dependent phenotype have been isolated for their interaction with hypomorphic Smn mutations.…”

Section: The Drosophila Eye As Model System For Identifying Modifiersmentioning

confidence: 99%

“…SMN targets include mRNAs encoding two negative regulators of the abundance of p53 [23], a key driver of motor neuron death [24]. Another SMN target, Stasimon, plays a dual role by preserving the function of the sensory-motor circuit and by restricting phosphorylation-mediated p53 activation [25]. SMN also plays splicing-independent functions that are thought to contribute to the SMA phenotype.…”

Section: Introductionmentioning

confidence: 99%

Intimate functional interactions between TGS1 and the Smn complex revealed by an analysis of the Drosophila eye development

et al. 2020

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Trimethylguanosine synthase 1 (TGS1) is a conserved enzyme that mediates formation of the trimethylguanosine cap on several RNAs, including snRNAs and telomerase RNA. Previous studies have shown that TGS1 binds the Survival Motor Neuron (SMN) protein, whose deficiency causes spinal muscular atrophy (SMA). Here, we analyzed the roles of the Drosophila orthologs of the human TGS1 and SMN genes. We show that the Drosophila TGS1 protein (dTgs1) physically interacts with all subunits of the Drosophila Smn complex (Smn, Gem2, Gem3, Gem4 and Gem5), and that a human TGS1 transgene rescues the mutant phenotype caused by dTgs1 loss. We demonstrate that both dTgs1 and Smn are required for viability of retinal progenitor cells and that downregulation of these genes leads to a reduced eye size. Importantly, overexpression of dTgs1 partially rescues the eye defects caused by Smn depletion, and vice versa. These results suggest that the Drosophila eye model can be exploited for screens aimed at the identification of genes and drugs that modify the phenotypes elicited by Tgs1 and Smn deficiency. These modifiers could help to understand the molecular mechanisms underlying SMA pathogenesis and devise new therapies for this genetic disease.

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A survey of transcripts generated by spinal muscular atrophy genes

Singh

Ottesen

Singh

2020

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy

Cited by 9 publications

References 0 publications

TGS1 controls snRNA 3’ end processing, prevents neurodegeneration and ameliorates SMN-dependent neurological phenotypes in vivo

TGS1 controls snRNA 3’ end processing, prevents neurodegeneration and ameliorates SMN-dependent neurological phenotypes in vivo

Intimate functional interactions between TGS1 and the Smn complex revealed by an analysis of the Drosophila eye development

A survey of transcripts generated by spinal muscular atrophy genes

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