The RNA binding KH domain of Spoonbill depletes pathogenic non-coding spinocerebellar ataxia 8 transcripts and suppresses neurodegeneration in Drosophila

Tripathi, Bipin Kumar; Surabhi, Satya; Bhaskar, Pradeep Kumar; Mukherjee, Ashim; Mutsuddi, Mousumi

doi:10.1016/j.bbadis.2016.06.008

Cited by 9 publications

(6 citation statements)

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“…Spoon exhibited a unique pattern of expression in larval brain and was specifically detected in the larval neuroblasts (Figure 5a As previously reported, Spoon suppresses SCA8 pathogenic RNA associated neurodegeneration via its KH domain (Mutsuddi et al, 2004, Tripathi et al, 2016. However, in combination with a single copy loss of function allele of prospero, suppression of SCA8 associated neurodegeneration by Spoon is inhibited ( Figure 6).…”

Section: R E Sults An D Discussionsupporting

confidence: 69%

“…SCA8 is a neurodegenerative disorder that is caused due to CTG expansion in human ATXN8OS gene. Expansion of the non‐coding RNA is the primary causal mechanism behind SCA8 pathogenesis (Mutsuddi et al, ; Tripathi, Surabhi, Bhaskar, Mukherjee, & Mutsuddi, ). As previously reported, Spoon suppresses SCA8 pathogenic RNA associated neurodegeneration via its KH domain (Mutsuddi et al, , Tripathi et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

“…Fly stocks were cultured on standard cornmeal/yeast/agar medium at 248C 6 18C. w 1118 , w; 1/1; UAS-HA-spoon (Tripathi et al, 2016) EP1400; 1/1; 1/1 (Bloomington 11236), sc; TRiP.GL00644; 1/1 (Bloomington 38205), w; 1/1; Pros 17 /TM6b,Tb (Bloomington 5458), w; 1/1; SCA8/TM6b,Tb (Mutsuddi et al, 2004). w; GMR-GAL4; 1/1, w; en-GAL4; 1/1 and w; 1/1; sgs-GAL4 were used in our study.…”

Section: Fly Stocks and Rearingmentioning

confidence: 99%

“…Immunoprecipitation of Spoon protein complex with anti-Spoon antibody followed by western blot with anti-Prospero antibody revealed that both the proteins are part of the same complex in the larval brain(Figure 5e).SCA8 is a neurodegenerative disorder that is caused due to CTG expansion in human ATXN8OS gene. Expansion of the non-coding RNA is the primary causal mechanism behind SCA8 pathogenesis(Mutsuddi et al, 2004;Tripathi, Surabhi, Bhaskar, Mukherjee, & Mutsuddi, 2016).…”

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confidence: 99%

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Interaction of Spoonbill with Prospero in Drosophila: Implications in neuroblast development

Tripathi

Das

Mukherjee

et al. 2017

Genesis

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Identification of Spoon as a suppressor of SCA8 associated neurodegeneration provides us a hint about its role in neuronal development and maintenance. However, a detailed molecular characterization of spoon has not yet been reported. Here, we describe spatial expression pattern of Spoon during Drosophila development. Quantitative real time-PCR and fluorescent RNA-RNA in situ hybridization indicate that Spoon is expressed at relatively high levels in larval brain and photoreceptors of eye-antennal discs. Immunostaining reveals that Spoon is subcellularly localized in the cytoplasm and is also membrane bound. Strong expression is also seen in adult ovary and testes. Spoon on immunostaining exhibits unique pattern of expression in larval brain. We observed that Spoon in the neuroblasts colocalizes with Prospero, a transcription factor regulating genes involved in neuroblast self-renewal or cell-cycle control. Co-immunoprecipitation suggests that Spoon and Prospero reside in the same protein complex. Using Drosophila model of SCA8 RNA neuropathy we have also shown that loss of Prospero hinders the suppression of SCA8 associated neurodegeneration by Spoonbill, suggesting Prospero and Spoon might genetically interact and function together. Our study presents Spoon as a novel interacting partner of Prospero and this might be critical in determining the polarized localization of cell fate determinants.

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Section: R E Sults An D Discussionsupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Section: Fly Stocks and Rearingmentioning

confidence: 99%

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confidence: 99%

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Interaction of Spoonbill with Prospero in Drosophila: Implications in neuroblast development

Tripathi

Das

Mukherjee

et al. 2017

Genesis

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“… 36 In another study, suppression of toxicity in an abnormal ATXN8OS transcript by a certain protein in vivo exerted a therapeutic effect. 37 Although the ATXN8OS gene, reported to have bidirectional transcripts, may have a more complex pathomechanism, 7 suppression of at least 1 pathologic pathway might help slow the disease process.…”

Section: Discussionmentioning

confidence: 99%

Noncoding repeat expansions for ALS in Japan are associated with the ATXN8OS gene

Hirano

Samukawa

Isono³

et al. 2018

Neurol Genet

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ObjectiveTo assess the contribution of noncoding repeat expansions in Japanese patients with amyotrophic lateral sclerosis (ALS).MethodsSporadic ALS in Western countries is frequently associated with noncoding repeat expansions in the C9ORF72 gene. Spinocerebellar ataxia type 8 (SCA8) is another noncoding repeat disease caused by expanded CTA/CTG repeats in the ATXN8OS gene. Although the involvement of upper and lower motor neurons in SCA8 has been reported, a positive association between SCA8 and ALS remains unestablished. Spinocerebellar ataxia type 36 is a recently identified disease caused by noncoding repeat expansions in the NOP56 gene and is characterized by motor neuron involvement. We collected blood samples from 102 Japanese patients with sporadic ALS and analyzed the ATXN8OS gene by the PCR–Sanger sequencing method and the C9ORF72 and NOP56 genes by repeat-primed PCR assay.ResultsThree patients with ALS (3%) had mutations in the ATXN8OS gene, whereas no patient had a mutation in the C9ORF72 or NOP56 gene. The mutation-positive patients were clinically characterized by neck weakness or bulbar-predominant symptoms. None of our patients had apparent cerebellar atrophy on MRI, but 2 had nonsymptomatic abnormalities in the white matter or putamen.ConclusionsOur finding reveals the importance of noncoding repeat expansions in Japanese patients with ALS and extends the clinical phenotype of SCA8. Three percent seems small but is still relatively large for Japan, considering that the most commonly mutated genes, including the SOD1 and SQSTM1 genes, only account for 2%–3% of sporadic patients each.

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Knockdown of genes involved in axonal transport enhances the toxicity of human neuromuscular disease‐linked MATR3 mutations in Drosophila

et al. 2020

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Mutations in the nuclear matrix protein Matrin 3 (MATR3) have been identified in amyotrophic lateral sclerosis and myopathy. To investigate the mechanisms underlying MATR3 mutations in neuromuscular diseases and efficiently screen for modifiers of MATR3 toxicity, we generated transgenic MATR3 flies. Our findings indicate that expression of wild‐type or mutant MATR3 in motor neurons reduces climbing ability and lifespan of flies, while their expression in indirect flight muscles (IFM) results in abnormal wing positioning and muscle degeneration. In both motor neurons and IFM, mutant MATR3 expression results in more severe phenotypes than wild‐type MATR3, demonstrating that the disease‐linked mutations confer pathogenicity. We conducted a targeted candidate screen for modifiers of the MATR3 abnormal wing phenotype and identified multiple enhancers involved in axonal transport. Knockdown of these genes enhanced protein levels and insolubility of mutant MATR3. These results suggest that accumulation of mutant MATR3 contributes to toxicity and implicate axonal transport dysfunction in disease pathogenesis.

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The RNA binding KH domain of Spoonbill depletes pathogenic non-coding spinocerebellar ataxia 8 transcripts and suppresses neurodegeneration in Drosophila

Cited by 9 publications

References 51 publications

Interaction of Spoonbill with Prospero in Drosophila: Implications in neuroblast development

Interaction of Spoonbill with Prospero in Drosophila: Implications in neuroblast development

Noncoding repeat expansions for ALS in Japan are associated with the ATXN8OS gene

Knockdown of genes involved in axonal transport enhances the toxicity of human neuromuscular disease‐linked MATR3 mutations in Drosophila

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