Mitochondrial Dysfunction Reveals the Role of mRNA Poly(A) Tail Regulation in Oculopharyngeal Muscular Dystrophy Pathogenesis
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{"title"=>"Mitochondrial Dysfunction Reveals the Role of mRNA Poly(A) Tail Regulation in Oculopharyngeal Muscular Dystrophy Pathogenesis", "type"=>"journal", "authors"=>[{"first_name"=>"Aymeric", "last_name"=>"Chartier", "scopus_author_id"=>"8921995500"}, {"first_name"=>"Pierre", "last_name"=>"Klein", "scopus_author_id"=>"56581206700"}, {"first_name"=>"Stéphanie", "last_name"=>"Pierson", "scopus_author_id"=>"56581665200"}, {"first_name"=>"Nicolas", "last_name"=>"Barbezier", "scopus_author_id"=>"23967694300"}, {"first_name"=>"Teresa", "last_name"=>"Gidaro", "scopus_author_id"=>"12788604900"}, {"first_name"=>"François", "last_name"=>"Casas", "scopus_author_id"=>"7006843569"}, {"first_name"=>"Steven", "last_name"=>"Carberry", "scopus_author_id"=>"55407647600"}, {"first_name"=>"Paul", "last_name"=>"Dowling", "scopus_author_id"=>"7101912158"}, {"first_name"=>"Laurie", "last_name"=>"Maynadier", "scopus_author_id"=>"56582227900"}, {"first_name"=>"Maëlle", "last_name"=>"Bellec", "scopus_author_id"=>"56581873600"}, {"first_name"=>"Martine", "last_name"=>"Oloko", "scopus_author_id"=>"56582175300"}, {"first_name"=>"Claude", "last_name"=>"Jardel", "scopus_author_id"=>"55994997900"}, {"first_name"=>"Bodo", "last_name"=>"Moritz", "scopus_author_id"=>"18133874600"}, {"first_name"=>"George", "last_name"=>"Dickson", "scopus_author_id"=>"7103204913"}, {"first_name"=>"Vincent", "last_name"=>"Mouly", "scopus_author_id"=>"7004550582"}, {"first_name"=>"Kay", "last_name"=>"Ohlendieck", "scopus_author_id"=>"7005597581"}, {"first_name"=>"Gillian", "last_name"=>"Butler-Browne", "scopus_author_id"=>"7006093638"}, {"first_name"=>"Capucine", "last_name"=>"Trollet", "scopus_author_id"=>"10641959800"}, {"first_name"=>"Martine", "last_name"=>"Simonelig", "scopus_author_id"=>"6701765150"}], "year"=>2015, "source"=>"PLoS Genetics", "identifiers"=>{"pmid"=>"25816335", "doi"=>"10.1371/journal.pgen.1005092", "sgr"=>"84926362619", "isbn"=>"1553-7404 (Electronic)\r1553-7390 (Linking)", "scopus"=>"2-s2.0-84926362619", "issn"=>"15537404", "pui"=>"603513962"}, "id"=>"d29aa7e4-7f5a-3a40-8076-a569dfce37d6", "abstract"=>"<title>Author Summary</title> <p>Oculopharyngeal muscular dystrophy is a genetic disease characterized by progressive degeneration of specific muscles, leading to ptosis (eyelid drooping), dysphagia (swallowing difficulties) and proximal limb weakness. The disease results from mutations in a nuclear protein called poly(A) binding protein nuclear 1 that is involved in polyadenylation of messenger RNAs (mRNAs) and poly(A) site selection. To address the molecular mechanisms involved in the disease, we have used two animal models (<italic>Drosophila</italic> and mouse) that recapitulate the features of this disorder. We show that oculopharyngeal muscular dystrophy pathogenesis depends on defects in poly(A) tail length regulation of specific mRNAs. Because poly(A) tails play an essential role in mRNA stability, these defects result in accelerated decay of these mRNAs. The affected mRNAs encode mitochondrial proteins, and mitochondrial activity is impaired in diseased muscles. These findings have important implications for the development of potential therapies for oculopharyngeal muscular dystrophy, and might be relevant to decipher the molecular mechanisms underlying other disorders that involve mitochondrial dysfunction.</p>", "link"=>"http://www.mendeley.com/research/mitochondrial-dysfunction-reveals-role-mrna-polya-tail-regulation-oculopharyngeal-muscular-dystrophy", "reader_count"=>35, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>6, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>1, "Student > Master"=>2, "Student > Bachelor"=>5, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>3}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>6, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>1, "Student > Master"=>2, "Student > Bachelor"=>5, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>3}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>7, "Agricultural and Biological Sciences"=>16, "Medicine and Dentistry"=>7, "Neuroscience"=>1, "Business, Management and Accounting"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Unspecified"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Neuroscience"=>{"Neuroscience"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>16}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>7}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"United States"=>1}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1993026"], "description"=>"<p>The first molecular defect in OPMD would be a general decrease in the cleavage/polyadenylation reaction resulting from affected PABPN1 function. This would not lead to a reduction of mRNA levels at steady-state for most mRNAs, but would lead to such a decrease for mRNAs actively deadenylated by Smg/CCR4-NOT, among which mRNAs involved in mitochondrial function. This would result in mitochondrial dysfunction and in turn affected muscle function. Additional mechanisms of mRNA regulation occurring downstream of the first defect in cleavage/polyadenylation are also expected to be involved. CPSF, Cleavage and polyadenylation specificity factor; CstF, Cleavage stimulation factor; PAP, poly(A) polymerase.</p>", "links"=>[], "tags"=>["ccr", "mRNAs encoding mitochondrial proteins", "cleavage", "poly", "Drosophila OPMD model uncovers", "deadenylation regulator Smaug", "pabpn", "candidate genes encoding RNA binding proteins", "role", "Oculopharyngeal Muscular Dystrophy Pathogenesis Oculopharyngeal", "mitochondrial dysfunction"], "article_id"=>1359258, "categories"=>["Biological Sciences"], "users"=>["Aymeric Chartier", "Pierre Klein", "Stéphanie Pierson", "Nicolas Barbezier", "Teresa Gidaro", "François Casas", "Steven Carberry", "Paul Dowling", "Laurie Maynadier", "Maëlle Bellec", "Martine Oloko", "Claude Jardel", "Bodo Moritz", "George Dickson", "Vincent Mouly", "Kay Ohlendieck", "Gillian Butler-Browne", "Capucine Trollet", "Martine Simonelig"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005092.g009", "stats"=>{"downloads"=>0, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Molecular_model_of_OPMD_/1359258", "title"=>"Molecular model of OPMD.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-27 04:22:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1993021"], "description"=>"<p>A) Quantification of mRNA levels in control and PABPN1-17ala-expressing thoraxes in the presence or absence of heterozygous <i>twin</i> or <i>smg</i> mutations at day 6, using RT-qPCR. mRNA levels were normalized to <i>Cpr100A</i> mRNA. Means of two biological replicates quantified three times. Error bars represent standard deviation. * <i>p</i>-value <0. 05, ** <i>p</i>-value <0.01, *** <i>p</i>-value <0.001, ns: not significant, using the Student’s t-Test. B) Confocal images of immunostaining of indirect flight muscles from wild type and <i>smg</i> mutant (<i>smg</i><sup><i>PL00423</i></sup><i>/Df(3L)scf-R6</i>) adult flies with anti-Smg (green). DNA was visualized with DAPI (blue). Smg protein levels were strongly reduced in <i>smg</i><sup><i>PL00423</i></sup><i>/Df(3L)scf-R6</i> muscles compared to wild-type muscles. Scale bars: 5 μm. C) Western blots of protein extracts from wild-type and <i>smg</i> mutant thoraxes revealed with guinea pig (gp) and rabbit (rb) anti-Smg, showing the presence of Smg and its lower level in <i>smg</i> mutant. α-Tubulin was used as a loading control. D) Smg immunoprecipitations (IP) in <i>UASp-CCR4-HA/Mhc-Gal4</i> adult thoraxes, either in the presence or the absence of RNase A. Mock IP was with rabbit IgG. Input is the protein extract prior to immunoprecipitation. Western blots revealed with anti-Smg, anti-HA and anti-PABP2, showing CCR4-HA co-precipitation and the lack of PABP2 co-precipitation. E) Quantification of mRNA enrichment in Smg IP using RT-qPCR. The ratio of mRNA/control mRNA was set to 1 in the mock IP (black line). Normalization was with <i>sop</i> mRNA. <i>RpL32</i> mRNA is a negative control, which is not enriched in Smg IP. Means are from two independent IP quantified three times. Error bars represent standard error to the mean. F) Means of SRE scores of mRNAs down-regulated in PABPN1-17ala-expressing muscles and annotated with the term \"mitochondrion\" compared to those of control mRNAs, in <i>Drosophila</i> (left panel) and mouse (right panel). Twenty times 98 <i>Drosophila</i> and 10 times 407 mouse control genes were used. Error bars represent standard deviation.</p>", "links"=>[], "tags"=>["ccr", "mRNAs encoding mitochondrial proteins", "cleavage", "poly", "Drosophila OPMD model uncovers", "deadenylation regulator Smaug", "pabpn", "candidate genes encoding RNA binding proteins", "role", "Oculopharyngeal Muscular Dystrophy Pathogenesis Oculopharyngeal", "mitochondrial dysfunction"], "article_id"=>1359253, "categories"=>["Biological Sciences"], "users"=>["Aymeric Chartier", "Pierre Klein", "Stéphanie Pierson", "Nicolas Barbezier", "Teresa Gidaro", "François Casas", "Steven Carberry", "Paul Dowling", "Laurie Maynadier", "Maëlle Bellec", "Martine Oloko", "Claude Jardel", "Bodo Moritz", "George Dickson", "Vincent Mouly", "Kay Ohlendieck", "Gillian Butler-Browne", "Capucine Trollet", "Martine Simonelig"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005092.g005", "stats"=>{"downloads"=>0, "page_views"=>26, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Smg_binds_to_mRNAs_encoding_mitochondrial_proteins_and_is_involved_in_mRNA_down_regulation_due_to_PABPN1_17ala_expression_/1359253", "title"=>"Smg binds to mRNAs encoding mitochondrial proteins and is involved in mRNA down-regulation due to PABPN1-17ala expression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-27 04:22:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1993020"], "description"=>"<p>A) Schematic representation of primers (arrows) used to quantify uncleaved pre-mRNA. B) Quantification of uncleaved pre-mRNAs in control and PABPN1-17ala-expressing thoraxes at day 2, using RT-qPCR. Uncleaved RNAs were normalized to <i>Cpr100A</i> uncleaved RNA. <i>Cpr100A</i> is expressed in the cuticle and its expression remains unaffected by expression of PABPN1-17ala in muscles. Means of three biological replicates quantified three times. For (B) and (C), error bars represent standard deviation. * <i>p</i>-value <0.05, ** <i>p</i>-value <0.01, *** <i>p</i>-value <0.001, ns: not significant, using the Student’s t-Test. C) Quantification of uncleaved pre-mRNAs in control (<i>w</i><sup><i>1118</i></sup>) and <i>Pabp2</i> (<i>Pabp2</i><sup><i>55</i></sup><i>/Df(2R)CA53</i>) mutant first instar larvae, using RT-qPCR. Uncleaved RNAs were normalized to <i>RpS6</i> uncleaved RNA. The levels of <i>RpS6</i> uncleaved RNA normalized to <i>sop</i> mRNA were unaffected in <i>Pabp2</i> mutant larvae (right panel). Means of three biological replicates quantified three times.</p>", "links"=>[], "tags"=>["ccr", "mRNAs encoding mitochondrial proteins", "cleavage", "poly", "Drosophila OPMD model uncovers", "deadenylation regulator Smaug", "pabpn", "candidate genes encoding RNA binding proteins", "role", "Oculopharyngeal Muscular Dystrophy Pathogenesis Oculopharyngeal", "mitochondrial dysfunction"], "article_id"=>1359252, "categories"=>["Biological Sciences"], "users"=>["Aymeric Chartier", "Pierre Klein", "Stéphanie Pierson", "Nicolas Barbezier", "Teresa Gidaro", "François Casas", "Steven Carberry", "Paul Dowling", "Laurie Maynadier", "Maëlle Bellec", "Martine Oloko", "Claude Jardel", "Bodo Moritz", "George Dickson", "Vincent Mouly", "Kay Ohlendieck", "Gillian Butler-Browne", "Capucine Trollet", "Martine Simonelig"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005092.g004", "stats"=>{"downloads"=>1, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Defective_cleavage_at_poly_A_sites_in_muscles_expressing_PABPN1_17ala_and_in_the_Pabp2_mutant_/1359252", "title"=>"Defective cleavage at poly(A) sites in muscles expressing PABPN1-17ala and in the <i>Pabp2</i> mutant.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-27 04:22:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1993017"], "description"=>"<p>A) Quantification of mitochondrial DNA (mtDNA) content in control and PABPN1-17ala- expressing thoraxes at day 2, using qPCR. Three mitochondrial genes (<i>mt</i>:<i>CoI</i>, <i>mt</i>:<i>CoII</i> and <i>mt</i>:<i>cyt-b</i>) were analysed. Mitochondrial DNA levels were normalized to <i>RpL32</i> DNA. Means are from three biological replicates, error bars represent standard deviation. ns: not significant, using the Student’s t-Test. B) Activities of mitochondrial respiratory chain complexes were analysed by spectrophotometry from control and PABPN1-17ala-expressing thoraxes (genotypes as in A). Means are from five biological replicates, error bars represent standard deviation. * <i>p</i>-value <0.05, *** <i>p</i>-value <0.001, ns: not significant, using the Student’s t-Test. C) Quantification of mRNA levels of transcription factors regulating mitochondrial function in control and PABPN1-17ala-expressing thoraxes at day 2, using RT-qPCR (genotypes as in A). mRNA levels were normalized to <i>sop</i> mRNA. Means are from two biological replicates quantified three times, error bars represent standard deviation. *** <i>p</i>-value <0.001, ns: not significant, using the Student’s t-Test. D) Overexpression of <i>ewg</i> and <i>dERR</i> genes reduces the wing posture phenotypes of flies expressing PABPN1-17ala. Wing posture phenotypes were scored at day 6, at 18°C from OPMD (<i>w</i><sup><i>1118</i></sup><i>; UAS-PABPN1-17ala/+; Mhc-Gal4/+</i>), OPMD; <i>OE-spargel</i> (<i>w</i><sup><i>1118</i></sup><i>; UAS-PABPN1-17ala/+; Mhc-Gal4/</i>s<i>pargel</i><sup><i>EY05931</i></sup>), OPMD; <i>OE-delg</i> (<i>w</i><sup><i>1118</i></sup><i>; UAS-PABPN1-17ala</i>, <i>UAS-delg-HA/+; Mhc-Gal4/+</i>), OPMD; <i>OE-ewg</i> (<i>w</i>, <i>ewg</i><sup><i>EY05137</i></sup><i>/Y; UAS-PABPN1-17ala/+; Mhc-Gal4/+</i>) and OPMD; <i>OE-dERR</i> (<i>w</i><sup><i>1118</i></sup><i>; UAS-PABPN1-17ala/+; Mhc-Gal4/dERR</i><sup><i>G4389</i></sup>) flies (n > 130). *** <i>p</i>-value <0.001, using the χ<sup>2</sup> test.</p>", "links"=>[], "tags"=>["ccr", "mRNAs encoding mitochondrial proteins", "cleavage", "poly", "Drosophila OPMD model uncovers", "deadenylation regulator Smaug", "pabpn", "candidate genes encoding RNA binding proteins", "role", "Oculopharyngeal Muscular Dystrophy Pathogenesis Oculopharyngeal", "mitochondrial dysfunction"], "article_id"=>1359249, "categories"=>["Biological Sciences"], "users"=>["Aymeric Chartier", "Pierre Klein", "Stéphanie Pierson", "Nicolas Barbezier", "Teresa Gidaro", "François Casas", "Steven Carberry", "Paul Dowling", "Laurie Maynadier", "Maëlle Bellec", "Martine Oloko", "Claude Jardel", "Bodo Moritz", "George Dickson", "Vincent Mouly", "Kay Ohlendieck", "Gillian Butler-Browne", "Capucine Trollet", "Martine Simonelig"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005092.g002", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Reduced_mitochondrial_activity_in_muscles_expressing_PABPN1_17ala_/1359249", "title"=>"Reduced mitochondrial activity in muscles expressing PABPN1-17ala.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-27 04:22:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1993016"], "description"=>"<p>A) Number of deregulated genes in the transcriptome of PABPN1-17ala-expressing muscles using microarrays. B) Venn’s diagram of overlapping down-regulated genes at days 2, 6 and 11. C) GO term enrichment in down-regulated genes in PABPN1-17ala-expressing muscles. D) Number of nuclear genes encoding mitochondrial respiratory chain complex subunits down-regulated in PABPN1-17ala-expressing muscles. E) Quantification of levels of mRNAs encoding mitochondrial respiratory chain subunits of complexes I and II in control and PABPN1-17ala-expressing muscles at day 2, using RT-qPCR. mRNA levels were normalized to <i>sop</i> mRNA. Similar results were obtained when normalization was with <i>Cpr100A</i> mRNA which is expressed in thorax cuticle. Means are from three biological replicates, error bars represent standard deviation. * <i>p</i>-value <0.05, *** <i>p</i>-value <0.001, ns: not significant, using the Student’s t-Test.</p>", "links"=>[], "tags"=>["ccr", "mRNAs encoding mitochondrial proteins", "cleavage", "poly", "Drosophila OPMD model uncovers", "deadenylation regulator Smaug", "pabpn", "candidate genes encoding RNA binding proteins", "role", "Oculopharyngeal Muscular Dystrophy Pathogenesis Oculopharyngeal", "mitochondrial dysfunction"], "article_id"=>1359248, "categories"=>["Biological Sciences"], "users"=>["Aymeric Chartier", "Pierre Klein", "Stéphanie Pierson", "Nicolas Barbezier", "Teresa Gidaro", "François Casas", "Steven Carberry", "Paul Dowling", "Laurie Maynadier", "Maëlle Bellec", "Martine Oloko", "Claude Jardel", "Bodo Moritz", "George Dickson", "Vincent Mouly", "Kay Ohlendieck", "Gillian Butler-Browne", "Capucine Trollet", "Martine Simonelig"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005092.g001", "stats"=>{"downloads"=>1, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Deregulation_of_the_mitochondrial_pathway_in_the_OPMD_Drosophila_model_/1359248", "title"=>"Deregulation of the mitochondrial pathway in the OPMD <i>Drosophila</i> model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-27 04:22:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1993025"], "description"=>"<p>A) Distribution of differentially expressed proteins from OPMD and control human muscle samples, following a quantitative label-free LC-MS profiling proteomic analysis. Proteins are sorted according to their GO terms in \"cellular component\" using DAVID. Each square represents a protein. The value of the fold change is color-coded. Yellow to red, over-expressed in OPMD samples (maximum 20-fold); blue, under-expressed in OPMD samples (minimum -20-fold). B) Number of subunits of the mitochondrial respiratory chain complexes down-regulated in OPMD patient muscle biopsies. C) Quantification of levels of mRNAs encoding mitochondrial respiratory chain subunits in control and OPMD patient muscle biopsies, using RT-qPCR. Normalization was with B2M (Beta-2 microglobulin) mRNA. Box plots are from 4–7 muscle biopsies, the median is indicated as an horizontal line within the box. * <i>p</i>-value <0.05 using the Student’s t-Test. For ATP5B and ATP5F1, the median is lower in OPMD than in control biopsies, although the difference is not recorded as significant. D) Quantification of mitochondrial DNA on muscle biopsies, using qPCR. The MT-RNR1 mitochondrial gene was quantified. Normalization was with B2M nuclear DNA. Means are from four biological replicates, error bars represent standard deviation. ns: not significant, using the Student’s t-Test.</p>", "links"=>[], "tags"=>["ccr", "mRNAs encoding mitochondrial proteins", "cleavage", "poly", "Drosophila OPMD model uncovers", "deadenylation regulator Smaug", "pabpn", "candidate genes encoding RNA binding proteins", "role", "Oculopharyngeal Muscular Dystrophy Pathogenesis Oculopharyngeal", "mitochondrial dysfunction"], "article_id"=>1359257, "categories"=>["Biological Sciences"], "users"=>["Aymeric Chartier", "Pierre Klein", "Stéphanie Pierson", "Nicolas Barbezier", "Teresa Gidaro", "François Casas", "Steven Carberry", "Paul Dowling", "Laurie Maynadier", "Maëlle Bellec", "Martine Oloko", "Claude Jardel", "Bodo Moritz", "George Dickson", "Vincent Mouly", "Kay Ohlendieck", "Gillian Butler-Browne", "Capucine Trollet", "Martine Simonelig"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005092.g008", "stats"=>{"downloads"=>0, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Decrease_of_mitochondrial_protein_levels_in_human_OPMD_muscle_biopsies_/1359257", "title"=>"Decrease of mitochondrial protein levels in human OPMD muscle biopsies.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-27 04:22:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1993023"], "description"=>"<p>A) Number of deregulated genes in A17.1 mouse skeletal muscles using microarrays. T1, 6 weeks; T2, 18 weeks; T3, 26 weeks. B) Venn diagram of overlapping down-regulated genes at T1, T2 and T3. C) Number of nuclear genes encoding mitochondrial respiratory chain complex subunits down-regulated in A17.1 mouse muscles. D) Quantification of levels of mRNAs encoding mitochondrial respiratory chain subunits in control (WT) and A17.1 quadriceps skeletal muscle at T1, using RT-qPCR. Normalization was with <i>Rplp0</i> mRNA. Means are from three biological replicates, error bars represent standard deviation. * <i>p</i>-value <0.05, ** <i>p</i>-value <0.01, *** <i>p</i>-value <0.001, using the Student’s t-Test. E) ePAT assays of mRNAs encoding mitochondrial proteins in control (WT) and A17.1 quadriceps skeletal muscles. Arrows indicate poly(A) tails of 12A. Accumulation of 12A poly(A) tails was visible in A17.1 muscles at T2 and/or T3. <i>RpL32</i> is a negative control mRNA encoding a ribosomal protein. Profiles of ePAT assays using the ImageJ software are shown.</p>", "links"=>[], "tags"=>["ccr", "mRNAs encoding mitochondrial proteins", "cleavage", "poly", "Drosophila OPMD model uncovers", "deadenylation regulator Smaug", "pabpn", "candidate genes encoding RNA binding proteins", "role", "Oculopharyngeal Muscular Dystrophy Pathogenesis Oculopharyngeal", "mitochondrial dysfunction"], "article_id"=>1359255, "categories"=>["Biological Sciences"], "users"=>["Aymeric Chartier", "Pierre Klein", "Stéphanie Pierson", "Nicolas Barbezier", "Teresa Gidaro", "François Casas", "Steven Carberry", "Paul Dowling", "Laurie Maynadier", "Maëlle Bellec", "Martine Oloko", "Claude Jardel", "Bodo Moritz", "George Dickson", "Vincent Mouly", "Kay Ohlendieck", "Gillian Butler-Browne", "Capucine Trollet", "Martine Simonelig"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005092.g007", "stats"=>{"downloads"=>2, "page_views"=>43, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Deregulation_of_the_mitochondrial_pathway_in_the_OPMD_mouse_model_/1359255", "title"=>"Deregulation of the mitochondrial pathway in the OPMD mouse model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-27 04:22:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1993022"], "description"=>"<p>A) Genetic rescue of wing position phenotypes with <i>twin</i><sup><i>KG00877</i></sup> hererozygous mutant. Percentage of wing posture defects in the presence or absence of <i>twin</i><sup><i>KG00877</i></sup>/+, scored at day 6. OPMD flies were <i>w</i><sup><i>1118</i></sup><i>; UAS-PABPN1-17ala/+; Mhc-Gal4/+</i> raised at 18°C. *** <i>p</i>-value <0.0001, using the χ<sup>2</sup> test. B) Immunostaining of indirect flight muscles from OPMD (<i>w</i><sup><i>1118</i></sup><i>; UAS-PABPN1-17ala/+; Mhc-Gal4/+)</i> and OPMD; <i>twin</i><sup><i>KG00877</i></sup><i>/+</i> (<i>w</i><sup><i>1118</i></sup><i>; UAS-PABPN1-17ala/+; Mhc-Gal4/twin</i><sup><i>KG00877</i></sup>) adult flies at day 6 with anti-PABPN1 (green), showing nuclear aggregates. DNA was visualized with DAPI (blue). Nuclei are outlined with a dotted line. C) Quantification of PABPN1 nuclear aggregates. (Top) Percentages of nuclei with a nuclear PABPN1 aggregate in OPMD and OPMD; <i>twin</i><sup><i>KG00877</i></sup><i>/+</i> indirect flight muscles (genotypes as in B) *** <i>p</i>-value <0.0001, using the χ<sup>2</sup> test. (Bottom) Quantification of nuclear aggregate areas. Each nuclear aggregate was delimited in a focal plan and the surface was calculated using ImageJ. Mean values of the areas with standard errors of the mean are indicated in arbitrary units Distribution of cross-sectional areas is shown as box plots (right), the median is indicated as an horizontal line within the box. ns: not significant, using the Student’s t-Test. Thoracic muscles were stained with anti-PABPN1 and DAPI and nuclear aggregates were visualized and scored using both staining. Quantification was from three independent experiments.</p>", "links"=>[], "tags"=>["ccr", "mRNAs encoding mitochondrial proteins", "cleavage", "poly", "Drosophila OPMD model uncovers", "deadenylation regulator Smaug", "pabpn", "candidate genes encoding RNA binding proteins", "role", "Oculopharyngeal Muscular Dystrophy Pathogenesis Oculopharyngeal", "mitochondrial dysfunction"], "article_id"=>1359254, "categories"=>["Biological Sciences"], "users"=>["Aymeric Chartier", "Pierre Klein", "Stéphanie Pierson", "Nicolas Barbezier", "Teresa Gidaro", "François Casas", "Steven Carberry", "Paul Dowling", "Laurie Maynadier", "Maëlle Bellec", "Martine Oloko", "Claude Jardel", "Bodo Moritz", "George Dickson", "Vincent Mouly", "Kay Ohlendieck", "Gillian Butler-Browne", "Capucine Trollet", "Martine Simonelig"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005092.g006", "stats"=>{"downloads"=>4, "page_views"=>66, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Nuclear_PABPN1_aggregates_in_the_OPMD_Drosophila_model_/1359254", "title"=>"Nuclear PABPN1 aggregates in the OPMD <i>Drosophila</i> model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-27 04:22:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1993018"], "description"=>"<p>A) Genetic rescue of wing position phenotypes with genes involved in poly(A) tail regulation. Percentage of wing posture defects in the presence or absence of heterozygous mutants, scored at day 6. OPMD flies were <i>w</i><sup><i>1118</i></sup><i>; Act88F-PABPN1-17ala/+</i> raised at 25°C. Note that OPMD phenotypes (affected wing posture) are not visible at day 2 with this transgene. **** <i>p</i>-value <0.0001, using the χ<sup>2</sup> test. B) Genetic screen with heterozygous mutants. Wing posture defects were scored at day 6. OPMD flies were <i>w</i><sup><i>1118</i></sup><i>; Act88F-PABPN1-17ala/+</i> raised at 25°C. <i>wispy</i> encodes a cytoplasmic poly(A) polymerase expressed in the female germline [<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005092#pgen.1005092.ref042\" target=\"_blank\">42</a>]. **** <i>p</i>-value <0.0001, *** <i>p</i>-value <0.001, ** <i>p</i>-value <0.01, ns: not significant, using the χ<sup>2</sup> test. C-D) PAT assays in control (<i>w</i><sup><i>1118</i></sup><i>; Mhc-Gal4/+</i>) and OPMD (<i>w</i><sup><i>1118</i></sup><i>; UAS-PABPN1-17ala/+; Mhc-Gal4/+</i>) adult thoraxes from flies raised at 18°C, at days 2 and 6. C) mRNAs encoding subunits of mitochondrial respiratory chain complexes. D) mRNAs encoding muscle sarcomeric proteins. Arrows indicate poly(A) tails of 12A. Profiles of PAT assays using the ImageJ software are shown.</p>", "links"=>[], "tags"=>["ccr", "mRNAs encoding mitochondrial proteins", "cleavage", "poly", "Drosophila OPMD model uncovers", "deadenylation regulator Smaug", "pabpn", "candidate genes encoding RNA binding proteins", "role", "Oculopharyngeal Muscular Dystrophy Pathogenesis Oculopharyngeal", "mitochondrial dysfunction"], "article_id"=>1359250, "categories"=>["Biological Sciences"], "users"=>["Aymeric Chartier", "Pierre Klein", "Stéphanie Pierson", "Nicolas Barbezier", "Teresa Gidaro", "François Casas", "Steven Carberry", "Paul Dowling", "Laurie Maynadier", "Maëlle Bellec", "Martine Oloko", "Claude Jardel", "Bodo Moritz", "George Dickson", "Vincent Mouly", "Kay Ohlendieck", "Gillian Butler-Browne", "Capucine Trollet", "Martine Simonelig"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005092.g003", "stats"=>{"downloads"=>0, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Poly_A_tail_length_regulation_plays_a_major_role_in_the_OPMD_Drosophila_model_/1359250", "title"=>"Poly(A) tail length regulation plays a major role in the OPMD <i>Drosophila</i> model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-27 04:22:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1993031", "https://ndownloader.figshare.com/files/1993032", "https://ndownloader.figshare.com/files/1993033", "https://ndownloader.figshare.com/files/1993034", "https://ndownloader.figshare.com/files/1993035", "https://ndownloader.figshare.com/files/1993036", "https://ndownloader.figshare.com/files/1993037", "https://ndownloader.figshare.com/files/1993038", "https://ndownloader.figshare.com/files/1993039", "https://ndownloader.figshare.com/files/1993040", "https://ndownloader.figshare.com/files/1993041", "https://ndownloader.figshare.com/files/1993042"], "description"=>"<div><p>Oculopharyngeal muscular dystrophy (OPMD), a late-onset disorder characterized by progressive degeneration of specific muscles, results from the extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice are established, the molecular mechanisms behind OPMD remain undetermined. Here, we show, using <i>Drosophila</i> and mouse models, that OPMD pathogenesis depends on affected poly(A) tail lengths of specific mRNAs. We identify a set of mRNAs encoding mitochondrial proteins that are down-regulated starting at the earliest stages of OPMD progression. The down-regulation of these mRNAs correlates with their shortened poly(A) tails and partial rescue of their levels when deadenylation is genetically reduced improves muscle function. Genetic analysis of candidate genes encoding RNA binding proteins using the <i>Drosophila</i> OPMD model uncovers a potential role of a number of them. We focus on the deadenylation regulator Smaug and show that it is expressed in adult muscles and specifically binds to the down-regulated mRNAs. In addition, the first step of the cleavage and polyadenylation reaction, mRNA cleavage, is affected in muscles expressing alanine-expanded PABPN1. We propose that impaired cleavage during nuclear cleavage/polyadenylation is an early defect in OPMD. This defect followed by active deadenylation of specific mRNAs, involving Smaug and the CCR4-NOT deadenylation complex, leads to their destabilization and mitochondrial dysfunction. These results broaden our understanding of the role of mRNA regulation in pathologies and might help to understand the molecular mechanisms underlying neurodegenerative disorders that involve mitochondrial dysfunction.</p></div>", "links"=>[], "tags"=>["ccr", "mRNAs encoding mitochondrial proteins", "cleavage", "poly", "Drosophila OPMD model uncovers", "deadenylation regulator Smaug", "pabpn", "candidate genes encoding RNA binding proteins", "role", "Oculopharyngeal Muscular Dystrophy Pathogenesis Oculopharyngeal", "mitochondrial dysfunction"], "article_id"=>1359263, "categories"=>["Biological Sciences"], "users"=>["Aymeric Chartier", "Pierre Klein", "Stéphanie Pierson", "Nicolas Barbezier", "Teresa Gidaro", "François Casas", "Steven Carberry", "Paul Dowling", "Laurie Maynadier", "Maëlle Bellec", "Martine Oloko", "Claude Jardel", "Bodo Moritz", "George Dickson", "Vincent Mouly", "Kay Ohlendieck", "Gillian Butler-Browne", "Capucine Trollet", "Martine Simonelig"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1005092.s001", "https://dx.doi.org/10.1371/journal.pgen.1005092.s002", "https://dx.doi.org/10.1371/journal.pgen.1005092.s003", "https://dx.doi.org/10.1371/journal.pgen.1005092.s004", "https://dx.doi.org/10.1371/journal.pgen.1005092.s005", "https://dx.doi.org/10.1371/journal.pgen.1005092.s006", "https://dx.doi.org/10.1371/journal.pgen.1005092.s007", "https://dx.doi.org/10.1371/journal.pgen.1005092.s008", "https://dx.doi.org/10.1371/journal.pgen.1005092.s009", "https://dx.doi.org/10.1371/journal.pgen.1005092.s010", "https://dx.doi.org/10.1371/journal.pgen.1005092.s011", "https://dx.doi.org/10.1371/journal.pgen.1005092.s012"], "stats"=>{"downloads"=>25, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mitochondrial_Dysfunction_Reveals_the_Role_of_mRNA_Poly_A_Tail_Regulation_in_Oculopharyngeal_Muscular_Dystrophy_Pathogenesis_/1359263", "title"=>"Mitochondrial Dysfunction Reveals the Role of mRNA Poly(A) Tail Regulation in Oculopharyngeal Muscular Dystrophy Pathogenesis", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-03-27 04:22:30"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"14", "full-text"=>"16", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2019", "month"=>"10"}
  • {"unique-ip"=>"15", "full-text"=>"14", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"47", "cited-by"=>"0", "year"=>"2019", "month"=>"12"}
  • {"unique-ip"=>"20", "full-text"=>"17", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"56", "cited-by"=>"0", "year"=>"2020", "month"=>"2"}
  • {"unique-ip"=>"20", "full-text"=>"16", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"49", "cited-by"=>"0", "year"=>"2020", "month"=>"3"}
  • {"unique-ip"=>"11", "full-text"=>"9", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"4"}
  • {"unique-ip"=>"16", "full-text"=>"13", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"5"}
  • {"unique-ip"=>"12", "full-text"=>"12", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"6"}
  • {"unique-ip"=>"7", "full-text"=>"6", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"7"}
  • {"unique-ip"=>"6", "full-text"=>"4", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"8"}
  • {"unique-ip"=>"15", "full-text"=>"16", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2020", "month"=>"9"}
  • {"unique-ip"=>"16", "full-text"=>"9", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2020", "month"=>"10"}

Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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