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
The motor neurodegenerative disease spinal muscular atrophy (SMA) is caused by alterations of the survival motor neuron 1 (SMN1) gene involved in RNA metabolism. Although the disease mechanisms are not completely elucidated, SMN protein deficiency leads to abnormal small nuclear ribonucleoproteins (...
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Frontiers Media S.A.
2020-04-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmolb.2020.00055/full |
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| author | Delphine Sapaly Perrine Delers Jennifer Coridon Badih Salman Franck Letourneur Florent Dumont Suzie Lefebvre |
| author_facet | Delphine Sapaly Perrine Delers Jennifer Coridon Badih Salman Franck Letourneur Florent Dumont Suzie Lefebvre |
| author_sort | Delphine Sapaly |
| collection | DOAJ |
| description | The motor neurodegenerative disease spinal muscular atrophy (SMA) is caused by alterations of the survival motor neuron 1 (SMN1) gene involved in RNA metabolism. Although the disease mechanisms are not completely elucidated, SMN protein deficiency leads to abnormal small nuclear ribonucleoproteins (snRNPs) assembly responsible for widespread splicing defects. SMN protein localizes in nuclear bodies that are lost in SMA and adult onset amyotrophic lateral sclerosis (ALS) patient cells harboring TDP-43 or FUS/TLS mutations. We previously reported that flunarizine recruits SMN into nuclear bodies and improves the phenotype of an SMA mouse model. However, the precise mode of action remains elusive. Here, a marked reduction of the integral components of the SMN complex is observed in severe SMA patient fibroblast cells. We show that flunarizine increases the protein levels of a subset of components of the SMN-Gemins complex, Gemins2-4, and markedly reduces the RNA and protein levels of the pro-oxydant thioredoxin-interacting protein (TXNIP) encoded by an mRNA target of Gemin5. We further show that SMN deficiency causes a dissociation of the localization of the SMN complex components from the same nuclear bodies. The accumulation of TDP-43 in SMN-positive nuclear bodies is also perturbed in SMA cells. Notably, TDP-43 is found to co-localize with SMN in nuclear bodies of flunarizine-treated SMA cells. Our findings indicate that flunarizine reverses cellular changes caused by SMN deficiency in SMA cells and further support the view of a common pathway in RNA metabolism underlying infantile and adult motor neuron diseases. |
| first_indexed | 2024-12-20T16:05:33Z |
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| language | English |
| last_indexed | 2024-12-20T16:05:33Z |
| publishDate | 2020-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-c4043ead41ba4398881b30204cdd50022022-12-21T19:34:10ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2020-04-01710.3389/fmolb.2020.00055516881The 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 DiseasesDelphine Sapaly0Perrine Delers1Jennifer Coridon2Badih Salman3Franck Letourneur4Florent Dumont5Suzie Lefebvre6INSERM UMR-S 1124, Toxicité Environnementale, Cibles Thérapeutiques, Signalisation Cellulaire et Biomarqueurs, Campus Saint-Germain-des-Prés, Université de Paris, Paris, FranceINSERM UMR-S 1124, Toxicité Environnementale, Cibles Thérapeutiques, Signalisation Cellulaire et Biomarqueurs, Campus Saint-Germain-des-Prés, Université de Paris, Paris, FranceBioMedTech Facilities INSERM US36 - CNRS UMS 2009, Campus Saint-Germain-des-Prés, Université de Paris, Paris, FranceINSERM UMR-S 1124, Toxicité Environnementale, Cibles Thérapeutiques, Signalisation Cellulaire et Biomarqueurs, Campus Saint-Germain-des-Prés, Université de Paris, Paris, FranceGenom’ic Platform, INSERM U1016, Institut Cochin, Paris, FranceGenom’ic Platform, INSERM U1016, Institut Cochin, Paris, FranceINSERM UMR-S 1124, Toxicité Environnementale, Cibles Thérapeutiques, Signalisation Cellulaire et Biomarqueurs, Campus Saint-Germain-des-Prés, Université de Paris, Paris, FranceThe motor neurodegenerative disease spinal muscular atrophy (SMA) is caused by alterations of the survival motor neuron 1 (SMN1) gene involved in RNA metabolism. Although the disease mechanisms are not completely elucidated, SMN protein deficiency leads to abnormal small nuclear ribonucleoproteins (snRNPs) assembly responsible for widespread splicing defects. SMN protein localizes in nuclear bodies that are lost in SMA and adult onset amyotrophic lateral sclerosis (ALS) patient cells harboring TDP-43 or FUS/TLS mutations. We previously reported that flunarizine recruits SMN into nuclear bodies and improves the phenotype of an SMA mouse model. However, the precise mode of action remains elusive. Here, a marked reduction of the integral components of the SMN complex is observed in severe SMA patient fibroblast cells. We show that flunarizine increases the protein levels of a subset of components of the SMN-Gemins complex, Gemins2-4, and markedly reduces the RNA and protein levels of the pro-oxydant thioredoxin-interacting protein (TXNIP) encoded by an mRNA target of Gemin5. We further show that SMN deficiency causes a dissociation of the localization of the SMN complex components from the same nuclear bodies. The accumulation of TDP-43 in SMN-positive nuclear bodies is also perturbed in SMA cells. Notably, TDP-43 is found to co-localize with SMN in nuclear bodies of flunarizine-treated SMA cells. Our findings indicate that flunarizine reverses cellular changes caused by SMN deficiency in SMA cells and further support the view of a common pathway in RNA metabolism underlying infantile and adult motor neuron diseases.https://www.frontiersin.org/article/10.3389/fmolb.2020.00055/fullneurodegenerative disordersspinal muscular atrophyamyotrophic lateral sclerosisRNA metabolismnuclear bodiesSMN complex |
| spellingShingle | Delphine Sapaly Perrine Delers Jennifer Coridon Badih Salman Franck Letourneur Florent Dumont Suzie Lefebvre 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 Frontiers in Molecular Biosciences neurodegenerative disorders spinal muscular atrophy amyotrophic lateral sclerosis RNA metabolism nuclear bodies SMN complex |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | neurodegenerative disorders spinal muscular atrophy amyotrophic lateral sclerosis RNA metabolism nuclear bodies SMN complex |
| url | https://www.frontiersin.org/article/10.3389/fmolb.2020.00055/full |
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