Mitochondrial Complex 1 Inhibition Increases 4-Repeat Isoform Tau by SRSF2 Upregulation
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{"title"=>"Mitochondrial complex 1 inhibition increases 4-Repeat isoform tau by SRSF2 upregulation", "type"=>"journal", "authors"=>[{"first_name"=>"Julius", "last_name"=>"Bruch", "scopus_author_id"=>"56419554600"}, {"first_name"=>"Hong", "last_name"=>"Xu", "scopus_author_id"=>"56419075900"}, {"first_name"=>"Anderson", "last_name"=>"De Andrade", "scopus_author_id"=>"56003342500"}, {"first_name"=>"Günter", "last_name"=>"Höglinger", "scopus_author_id"=>"6602778605"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84913553259", "pui"=>"600550273", "pmid"=>"25402454", "issn"=>"19326203", "scopus"=>"2-s2.0-84913553259", "doi"=>"10.1371/journal.pone.0113070"}, "id"=>"65376c2d-f6a1-3723-9b36-6495be9eff58", "abstract"=>"Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder characterised by intracellular aggregation of the microtubule-associated protein tau. The tau protein exists in 6 predominant isoforms. Depending on alternative splicing of exon 10, three of these isoforms have four microtubule-binding repeat domains (4R), whilst the others only have three (3R). In PSP there is an excess of the 4R tau isoforms, which are thought to contribute significantly to the pathological process. The cause of this 4R increase is so far unknown. Several lines of evidence link mitochondrial complex I inhibition to the pathogenesis of PSP. We demonstrate here for the first time that annonacin and MPP(+), two prototypical mitochondrial complex I inhibitors, increase the 4R isoforms of tau in human neurons. We show that the splicing factor SRSF2 is necessary to increase 4R tau with complex I inhibition. We also found SRSF2, as well as another tau splicing factor, TRA2B, to be increased in brains of PSP patients. Thereby, we provide new evidence that mitochondrial complex I inhibition may contribute as an upstream event to the pathogenesis of PSP and suggest that splicing factors may represent an attractive therapeutic target to intervene in the disease process.", "link"=>"http://www.mendeley.com/research/mitochondrial-complex-1-inhibition-increases-4repeat-isoform-tau-srsf2-upregulation", "reader_count"=>25, "reader_count_by_academic_status"=>{"Student > Doctoral Student"=>2, "Researcher"=>6, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>1, "Student > Master"=>4, "Student > Bachelor"=>4, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Student > Doctoral Student"=>2, "Researcher"=>6, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>1, "Student > Master"=>4, "Student > Bachelor"=>4, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>10, "Medicine and Dentistry"=>5, "Neuroscience"=>2, "Chemistry"=>1, "Psychology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Neuroscience"=>{"Neuroscience"=>2}, "Chemistry"=>{"Chemistry"=>1}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>10}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>1}}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1797460"], "description"=>"<p>A) Quantitative PCR results for 9 different splicing factors known to have an effect on exon 10 alternative splicing (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113070#pone-0113070-t002\" target=\"_blank\">table 2</a>). Data shown are relative quantities compared to untreated cells (dotted line). Only SRSF2 was elevated significantly with annonacin treatment. All other splicing factors tested were not significantly elevated. 3 biological repeats with 3 technical repeats each. ***: p<0.001, *: p<0.05 vs. untreated control (2-way ANOVA with Sidak's post-hoc test). B) Quantitative PCR results for LUHMES cells on day 10 post differentiation treated with SRSF2 knockdown siRNA for 10 days and/or with annonacin for 48 h. 3 biological repeats with 3 technical repeats each. ***: p<0.001 vs. untreated control (dotted line); ###: p<0.001 (2-way ANOVA with Sidak's post-hoc test). C) Quantitative PCR results for the 4 splicing factors known to increase MAPT exon 10 inclusion in <i>locus coeruleus</i> tissue of four PSP patients and five controls without neurodegenerative diseases. 3 biological repeats with 3 technical repeats each. #: p<0.05, ##: p<0.01 (2-way ANOVA with Sidak's post-hoc test).</p>", "links"=>[], "tags"=>["SRSF 2 Upregulation Progressive Supranuclear Palsy", "4 R tau isoforms", "Tau protein", "neurodegenerative disorder characterised", "evidence link mitochondrial", "Several lines", "factor SRSF 2", "inhibition", "intracellular aggregation", "increase 4 R tau", "4 R isoforms", "4 R increase", "TRA 2B", "PSP patients", "disease process", "mpp"], "article_id"=>1244240, "categories"=>["Biological Sciences"], "users"=>["Julius Bruch", "Hong Xu", "Anderson De Andrade", "Günter Höglinger"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0113070.g002", "stats"=>{"downloads"=>1, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SRSF2_is_a_Critical_Player_in_Annonacin_Mediated_Tau_Alternative_Splicing_/1244240", "title"=>"SRSF2 is a Critical Player in Annonacin Mediated Tau Alternative Splicing.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-17 03:19:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/1797462"], "description"=>"<p>A) ATP concentration and MTT cell viability in LUHMES cells as measured by the MTT assay for different concentrations of 6-OHDA. Treatment was for 48 h from day 8–10 post differentiation. n = 12. B) ATP concentration and MTT cell viability in LUHMES cells as measured by the MTT assay for different concentrations of MPP+. Treatment was for 48 h from day 8–10 post differentiation. n = 12. C) Quantitative PCR results of MAPT splicing variants for LUHMES cells treated with 10 µM MPP<sup>+</sup> for 48 h from day 8–10 post differentiation. 3 biological repeats with 3 technical repeats each. **: p<0.01 vs. untreated cells (dotted line), (2-way ANOVA with Sidak's post-hoc test). D) Quantitative PCR results of MAPT splicing variants for LUHMES cells treated with 20 µM 6-OHDA for 48 h from day 8–10 post differentiation. 3 biological repeats with 3 technical repeats each. *: p<0.05 vs. untreated cells (dotted line), (2-way ANOVA with Sidak's post-hoc test). E) Quantitative PCR results of MAPT splicing variants for LUHMES cells starved of nutrients and glucose for 24 h from day 8–9 post differentiation. 3 biological repeats with 3 technical repeats each. *: p<0.05 vs. untreated cells (dotted line), (2-way ANOVA with Sidak's post-hoc test). F) Quantitative PCR results of SRSF2 for LUHMES cells treated with 10 µM MPP<sup>+</sup> or 20 µM 6-OHDA for 48 h from day 8–10 post differentiation or starved for 24 h from day 8–9 post differentiation. 3 biological repeats with 3 technical repeats each. *: p<0.05, **: p<0.01 vs. untreated cells (dotted line), (2-way ANOVA with Sidak's post-hoc test).</p>", "links"=>[], "tags"=>["SRSF 2 Upregulation Progressive Supranuclear Palsy", "4 R tau isoforms", "Tau protein", "neurodegenerative disorder characterised", "evidence link mitochondrial", "Several lines", "factor SRSF 2", "inhibition", "intracellular aggregation", "increase 4 R tau", "4 R isoforms", "4 R increase", "TRA 2B", "PSP patients", "disease process", "mpp"], "article_id"=>1244242, "categories"=>["Biological Sciences"], "users"=>["Julius Bruch", "Hong Xu", "Anderson De Andrade", "Günter Höglinger"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0113070.g003", "stats"=>{"downloads"=>2, "page_views"=>54, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_4R_Isoform_Shift_Can_Be_Reproduced_with_Another_Complex_I_Inhibitor_but_not_with_the_Oxidative_Stressor_6_OHDA_/1244242", "title"=>"The 4R Isoform Shift Can Be Reproduced with Another Complex I Inhibitor but not with the Oxidative Stressor 6-OHDA.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-17 03:19:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/1797464"], "description"=>"<p>A) 4R isoform protein is upregulated with MPP<sup>+</sup> treatment. Western blot for 3R and 4R isoforms of tau protein, as well as total tau (detected with the HT7 antibody). LUHMES cells were either left untreated or treated with 10 µM MPP<sup>+</sup>. Actin was used as loading control. B) Quantification of <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113070#pone-0113070-g001\" target=\"_blank\">figure 1G</a>. Results show the relative quantity compared to the untreated control cells (dotted line). 3 biological repeats. ***: p<0.001 vs. untreated cells (2-way ANOVA with Sidak's post-hoc test).</p>", "links"=>[], "tags"=>["SRSF 2 Upregulation Progressive Supranuclear Palsy", "4 R tau isoforms", "Tau protein", "neurodegenerative disorder characterised", "evidence link mitochondrial", "Several lines", "factor SRSF 2", "inhibition", "intracellular aggregation", "increase 4 R tau", "4 R isoforms", "4 R increase", "TRA 2B", "PSP patients", "disease process", "mpp"], "article_id"=>1244244, "categories"=>["Biological Sciences"], "users"=>["Julius Bruch", "Hong Xu", "Anderson De Andrade", "Günter Höglinger"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0113070.g004", "stats"=>{"downloads"=>2, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_4R_Isoform_was_upregulated_in_the_protein_level_with_MPP_treatment_/1244244", "title"=>"The 4R Isoform was upregulated in the protein level with MPP<sup>+</sup> treatment.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-17 03:19:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/1797465"], "description"=>"<p>Primary Antibody Concentrations Used.</p>", "links"=>[], "tags"=>["SRSF 2 Upregulation Progressive Supranuclear Palsy", "4 R tau isoforms", "Tau protein", "neurodegenerative disorder characterised", "evidence link mitochondrial", "Several lines", "factor SRSF 2", "inhibition", "intracellular aggregation", "increase 4 R tau", "4 R isoforms", "4 R increase", "TRA 2B", "PSP patients", "disease process", "mpp"], "article_id"=>1244245, "categories"=>["Biological Sciences"], "users"=>["Julius Bruch", "Hong Xu", "Anderson De Andrade", "Günter Höglinger"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0113070.t001", "stats"=>{"downloads"=>5, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Primary_Antibody_Concentrations_Used_/1244245", "title"=>"Primary Antibody Concentrations Used.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-11-17 03:19:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/1797466"], "description"=>"<p>Source: Adapted from <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113070#pone.0113070-Liu1\" target=\"_blank\">[2]</a>.</p><p>Overview of the splicing factors known to influence MAPT exon 10 alternative splicing.</p>", "links"=>[], "tags"=>["SRSF 2 Upregulation Progressive Supranuclear Palsy", "4 R tau isoforms", "Tau protein", "neurodegenerative disorder characterised", "evidence link mitochondrial", "Several lines", "factor SRSF 2", "inhibition", "intracellular aggregation", "increase 4 R tau", "4 R isoforms", "4 R increase", "TRA 2B", "PSP patients", "disease process", "mpp"], "article_id"=>1244246, "categories"=>["Biological Sciences"], "users"=>["Julius Bruch", "Hong Xu", "Anderson De Andrade", "Günter Höglinger"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0113070.t002", "stats"=>{"downloads"=>4, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Overview_of_the_splicing_factors_known_to_influence_MAPT_exon_10_alternative_splicing_/1244246", "title"=>"Overview of the splicing factors known to influence MAPT exon 10 alternative splicing.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-11-17 03:19:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/1797468"], "description"=>"<p>Overview of Human Tissue Used.</p>", "links"=>[], "tags"=>["SRSF 2 Upregulation Progressive Supranuclear Palsy", "4 R tau isoforms", "Tau protein", "neurodegenerative disorder characterised", "evidence link mitochondrial", "Several lines", "factor SRSF 2", "inhibition", "intracellular aggregation", "increase 4 R tau", "4 R isoforms", "4 R increase", "TRA 2B", "PSP patients", "disease process", "mpp"], "article_id"=>1244248, "categories"=>["Biological Sciences"], "users"=>["Julius Bruch", "Hong Xu", "Anderson De Andrade", "Günter Höglinger"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0113070.t003", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Overview_of_Human_Tissue_Used_/1244248", "title"=>"Overview of Human Tissue Used.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-11-17 03:19:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/1797459"], "description"=>"<p>A) LUHMES neurons were treated with different concentrations of annonacin for 48 h from day 8–10 post differentiation (n = 12). The MTT test, a measure for mitochondrial reducing function, and ATP concentration, are expressed as a relative percentage compared to untreated control cells. B) 4R isoform (exon 10) mRNA is upregulated with annonacin treatment. Quantitative PCR results showing the relative quantity of mRNA for different <i>MAPT</i> splicing variants in cells treated with 25 nM annonacin for 48 h from day 8–10 post differentiation compared to untreated cells (dotted line). 3 biological repeats with 3 technical repeats each. ***: p<0.001, *: p<0.05 vs. untreated cells (2-way ANOVA with Sidak's post-hoc test). C) 4R isoform protein is upregulated with annonacin treatment. Western blot for 3R and 4R isoforms of tau protein, as well as total tau (detected with the HT7 antibody). LUHMES cells were either left untreated or treated with 25 nM annonacin. Actin was used as loading control. D) Quantification of <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113070#pone-0113070-g001\" target=\"_blank\">figure 1C</a>. Results show the relative quantity (fold-change) compared to untreated control cells (relative quantity  = 1, represented by dotted line). 3 biological repeats. ***: p<0.001 vs. untreated cells (2-way ANOVA with Sidak's post-hoc test).</p>", "links"=>[], "tags"=>["SRSF 2 Upregulation Progressive Supranuclear Palsy", "4 R tau isoforms", "Tau protein", "neurodegenerative disorder characterised", "evidence link mitochondrial", "Several lines", "factor SRSF 2", "inhibition", "intracellular aggregation", "increase 4 R tau", "4 R isoforms", "4 R increase", "TRA 2B", "PSP patients", "disease process", "mpp"], "article_id"=>1244239, "categories"=>["Biological Sciences"], "users"=>["Julius Bruch", "Hong Xu", "Anderson De Andrade", "Günter Höglinger"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0113070.g001", "stats"=>{"downloads"=>2, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Annonacin_Causes_an_Upregulation_of_the_4R_Isoforms_of_Tau_/1244239", "title"=>"Annonacin Causes an Upregulation of the 4R Isoforms of Tau.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-17 03:19:17"}

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Relative Metric

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