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{"title"=>"TDP-43-mediated neuron loss In Vivo requires RNA-binding activity", "type"=>"journal", "authors"=>[{"first_name"=>"Aaron", "last_name"=>"Voigt", "scopus_author_id"=>"7102088269"}, {"first_name"=>"David", "last_name"=>"Herholz", "scopus_author_id"=>"36552532400"}, {"first_name"=>"Fabienne C.", "last_name"=>"Fiesel", "scopus_author_id"=>"24179392800"}, {"first_name"=>"Kavita", "last_name"=>"Kaur", "scopus_author_id"=>"36552353200"}, {"first_name"=>"Daniel", "last_name"=>"Müller", "scopus_author_id"=>"57199771930"}, {"first_name"=>"Peter", "last_name"=>"Karsten", "scopus_author_id"=>"6602400574"}, {"first_name"=>"Stephanie S.", "last_name"=>"Weber", "scopus_author_id"=>"26667281600"}, {"first_name"=>"Philipp J.", "last_name"=>"Kahle", "scopus_author_id"=>"7003861568"}, {"first_name"=>"Till", "last_name"=>"Marquardt", "scopus_author_id"=>"7004604110"}, {"first_name"=>"Jörg B.", "last_name"=>"Schulz", "scopus_author_id"=>"7201479829"}], "year"=>2010, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-77957918535", "sgr"=>"77957918535", "pui"=>"359761525", "isbn"=>"1932-6203 (Electronic)\\n1932-6203 (Linking)", "pmid"=>"20806063", "doi"=>"10.1371/journal.pone.0012247"}, "id"=>"0ac44601-3d84-3f65-adb9-9f85219ae599", "abstract"=>"Alteration and/or mutations of the ribonucleoprotein TDP-43 have been firmly linked to human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The relative impacts of TDP-43 alteration, mutation, or inherent protein function on neural integrity, however, remain less clear--a situation confounded by conflicting reports based on transient and/or random-insertion transgenic expression. We therefore performed a stringent comparative investigation of impacts of these TDP-43 modifications on neural integrity in vivo. To achieve this, we systematically screened ALS/FTLD-associated and synthetic TDP-43 isoforms via same-site gene insertion and neural expression in Drosophila; followed by transposon-based motor neuron-specific transgenesis in a chick vertebrate system. Using this bi-systemic approach we uncovered a requirement of inherent TDP-43 RNA-binding function--but not ALS/FTLD-linked mutation, mislocalization, or truncation--for TDP-43-mediated neurotoxicity in vivo.", "link"=>"http://www.mendeley.com/research/tdp43mediated-neuron-loss-vivo-requires-rnabinding-activity", "reader_count"=>97, "reader_count_by_academic_status"=>{"Unspecified"=>4, "Professor > Associate Professor"=>3, "Researcher"=>27, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>32, "Student > Postgraduate"=>5, "Student > Master"=>9, "Other"=>3, "Student > Bachelor"=>7, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>4, "Professor > Associate Professor"=>3, "Researcher"=>27, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>32, "Student > Postgraduate"=>5, "Student > Master"=>9, "Other"=>3, "Student > Bachelor"=>7, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>4, "Biochemistry, Genetics and Molecular Biology"=>10, "Agricultural and Biological Sciences"=>65, "Medicine and Dentistry"=>15, "Neuroscience"=>2, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>15}, "Neuroscience"=>{"Neuroscience"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>65}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>10}, "Unspecified"=>{"Unspecified"=>4}}, "reader_count_by_country"=>{"Canada"=>1, "United States"=>1, "United Kingdom"=>4, "Spain"=>2}, "group_count"=>1}

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• {"type"=>"COMMENT", "annotationUri"=>"info:doi/10.1371/annotation/2d38a039-d2d6-4489-bd31-4a166ff65e16", "title"=>"About the results and conclusions", "body"=>"I like your paper, specially for the controversial aspects.\nI have some comments and questions about the results:\n1) In the figure 1 said that two CTF are analyzed but is not specify in the results. Is used the 206-424 or the 174-414? or both?\n2) Figure 2. Why the levels of endogenous TDP-43 are so low in the transfected cells (ex. 2b or 2c) compared with unstranfected control (fig.2a)? different laser intensities? different gain? is not specified in the text.\n3) Figure 5Bii. The statistics analysis is not clear. If each condition is compared with the vector bar I don't believe that the difference between CTF/NTF and vector are not significant. But this does not affect the interpretation of the data. However, in 5Cii the statics looks according the graph.\n4) Why in the figure 3 the co-localization in Drosophila between nuclear TDP-43 and DNA look so poor?\n\nAbout the conclusions:\nI don't know if the title of the paper is completely demonstrated. An important part of the conclusions are based in the work with FFLL mutant. But these mutations does not eliminate completely the RNA binding activity of TDP-43. In fact, in the figure 1B can be observed a low RNA binding activity with (UG)12. Has been demonstrated that several mutants with low bound to (UG)12 have still a significant binding activity with other RNA targets. I missed in the paper a deletion (total or partial) of RNA binding domain to support your main finding. \nPersonally, I think that the most important implication of the paper is not discussed. I think that these results suggest that the mutations of TDP-43 are not the cause of ALS. Figure 4a clearly supports this hypothesis. You show clearly that RNA-binding activity and a complete protein is necessary for the toxic effect of TDP-43. But, at the same time you show that the most toxic protein is the TDP-43wt, some mutations in fact have an important protector effect compared with the wt. This is according with the hypothesis that TDP-43 mutants are only polymorphism observed in the population and are not related with the cause of the pathology. May be, actually,they could protect of the toxic effects of the mis-regulated TDP-43 in ALS. ", "isRemoved"=>false, "created"=>"2010-09-03T14:32:32Z", "lastModified"=>"2010-09-03T14:32:32Z", "creator"=>{"userId"=>"61175"}, "highlightedText"=>"", "competingInterestStatement"=>{"creatorWasPrompted"=>true, "hasCompetingInterests"=>false}, "parentArticle"=>{"doi"=>"info:doi/10.1371/journal.pone.0012247", "state"=>"published", "journals"=>{"PLoSONE"=>{"journalKey"=>"PLoSONE", "eIssn"=>"1932-6203", "title"=>"PLOS ONE"}}}, "replyTreeSize"=>1, "mostRecentActivity"=>"2010-09-14T15:35:15Z", "replies"=>[{"type"=>"REPLY", "parentID"=>4027, "annotationUri"=>"info:doi/10.1371/reply/1294e47c-df53-44a8-9adc-25f5308a2f9a", "title"=>"RE: About the results and conclusions", "body"=>"Dear Dr. Droppelmann,\nthank you for your interest in our manuscript. In the following I will try to answer your questions:\n\n\"I like your paper, specially for the controversial aspects.\u2028I have some comments and questions about the results:\u20281) In the figure 1 said that two CTF are analyzed but is not specify in the results. Is used the 206-424 or the 174-414? or both?\"\n\nCTF 206-414 was used in chick, CTF 174-414 was used in flies. The reason is simple. We had generated CTF174-414 based on an educated guess, and generated the TDP-43CTF transgenic flies based on this fragment. Later, CTF 206-414 was reported to represent the dominant truncation fragment in ALS patients. From this point onwards, we consequently used this particular fragment, such as the eventual chick experiments. We assume that the near absence of toxicity of CTF observed in both systems is due to the principal equivalence of the two versions. Thus, so far, we did not generate new transgenic fly lines based on the CTF 206-414 version that may more accurately reflect the CTF accumulating in ALS/FTLD.\n\n\"\u20282) Figure 2. Why the levels of endogenous TDP-43 are so low in the transfected cells (ex. 2b or 2c) compared with unstranfected control (fig.2a)? different laser intensities? different gain? is not specified in the text.\u2028\"\n\nYou are right that the levels of endogenous TDP-43 look lower in cells that have been transfected compared to untransfected cells. However, this is not the case. We have used less exposure time to visualize transfected cells, since the TDP-43 antibody also recognizes transfected TDP-43 and similar exposure times would have caused the images of transfected cells to be oversaturated.\n\n\"3) Figure 5Bii. The statistics analysis is not clear. If each condition is compared with the vector bar I don't believe that the difference between CTF/NTF and vector are not significant. But this does not affect the interpretation of the data. However, in 5Cii the statics looks according the graph.\u2028\"\n\nFor each construct MN loss (%) was the ratio between Isl1/2+ cells in the motor column of control (non-electroporated) and the electroporated hemicord. “Significance” was calculated based on the thus determined MN loss (%) for each TDP-43 construct compared to the MN loss (%) obtained with the vector control. Since due to technical reasons DNA electroporation by itself was observed to trigger a small hike in MN loss on the electroporated side, this more accurately reflected ‘true’ MN loss due to TDP-43 activity than by calculating the significance based on comparing electroporated vs. non-electroporated side for each construct. \nNTF/CTF showed slightly significance calculated thus by t-test; but due to the specific experimental setup we assume that the differences are not suficient to relate this to any specific differences in the activity of these constructs compared to say “FFLL”. We conclude that the calculated significances for NTF/CTF, but not FFLL are due to the small ‘experiment-to-experiment variation’ inherent to the method based on transient transfection. Such subtle differences can only be meaningfully resolved by assuring near-equalized and stable expression, such as achieved by single-site insertion transgenes.\n\n\"4) Why in the figure 3 the co-localization in Drosophila between nuclear TDP-43 and DNA look so poor?\u2028\"\n\nIn the presented confocal sections, not all cells have the same level of TDP-43 expression (according to specification in development), this is why some nuclei do not stain as robust for TDP-43. The co-localization with DNA is obvious, although might be even better seen by looking at 3D data of the entire confocal Z-stack. Compared to cytoplasmically localized TDP-43[∆NLS], however, we think the difference is obvious. In addition, we provide additional pictures in figure S1. Herein, in register with the large cell and nucleus size of the salivary gland cells co-localization becomes more obvious. \n\n\"About the conclusions:\u2028I don't know if the title of the paper is completely demonstrated. An important part of the conclusions are based in the work with FFLL mutant. But these mutations do not eliminate completely the RNA binding activity of TDP-43. In fact, in the figure 1B can be observed a low RNA binding activity with (UG)12. Has been demonstrated that several mutants with low bound to (UG)12 have still a significant binding activity with other RNA targets. I missed in the paper a deletion (total or partial) of RNA binding domain to support your main finding.\"\n\nYou are right, we do not include a construct which selectively eliminates the activity by both RRMs. We mention precisely this point in the manuscript: ”At present, however, we cannot strictly exclude that TDP-43[FFLL] may retain residual RNA/DNA binding activity exerted by the remaining first RRM, which may underlay the slightly higher toxicity of TDP-43[FFLL] compared to TDP-43[CTF]. However, since “CTF” lacks RRM1 and is not toxic, this in essence supports our findings with “FFLL”; especially since RRM1 seems to account for the vast majority of (UG)12 RNA binding. Moreover, our data also suggests that not only RNA-binding is required to facilitate toxicity, since “NTF” (which is nuclear localized, possesses both RRMs, but selectively lacks the C-terminal segment) did not display any detectable toxicity when expressed in chick motor neurons. We think it is likely that neurotoxicity exerted by TDP-43 requires both, RRM-mediated RNA binding activity, plus the C-terminal segment - and that this may reflect the necessity to couple RNA-bound TDP-43 to other proteins relevant at least for over-expression-driven toxicity.\n\n\"Personally, I think that the most important implication of the paper is not discussed. I think that these results suggest that the mutations of TDP-43 are not the cause of ALS. Figure 4a clearly supports this hypothesis. You show clearly that RNA-binding activity and a complete protein is necessary for the toxic effect of TDP-43. But, at the same time you show that the most toxic protein is the TDP-43wt, some mutations in fact have an important protector effect compared with the wt. This is according with the hypothesis that TDP-43 mutants are only polymorphism observed in the population and are not related with the cause of the pathology. May be, actually, they could protect of the toxic effects of the mis-regulated TDP-43 in ALS.\"\n\nThis is an intriguing and of course provocative interpretation of the results presented by us. However, we think more work has to be done to finally clarify this issue. We think our data shows that most of the model systems used so far (or the way in which they are widely used) to infer impacts of ALS-linked mutations may not be suitable to finally solve this problem. Proper analysis of familial TDP-43 linked ALS cases will hopefully provide more convincing information then available at the moment. We think the ultimate acid test would be ‘knock-in’ experiments (e.g. in mouse) to introduce ALS-linked mutations into endogenous TDP-43 to unambiguously understand the role of these modifications in neurodegeneration in vivo.\n\nI hope we satisfactorily answered all of your questions and comments, and thank you for your insightful suggestions. \nSincerely,\nAaron Voigt\nTill Marquardt\nJörg B. Schulz\n", "isRemoved"=>false, "created"=>"2010-09-14T15:35:15Z", "lastModified"=>"2010-09-14T15:35:15Z", "creator"=>{"userId"=>"152423"}, "highlightedText"=>"", "competingInterestStatement"=>{"creatorWasPrompted"=>true, "hasCompetingInterests"=>false}, "parentArticle"=>{"doi"=>"info:doi/10.1371/journal.pone.0012247", "state"=>"published", "journals"=>{"PLoSONE"=>{"journalKey"=>"PLoSONE", "eIssn"=>"1932-6203", "title"=>"PLOS ONE"}}}, "replyTreeSize"=>0, "mostRecentActivity"=>"2010-09-14T15:35:15Z", "replies"=>[]}]}

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Figshare

• {"files"=>["https://ndownloader.figshare.com/files/835427"], "description"=>"<p>(A) TDP-43 expression reduces longevity in <i>Drosophila</i>. Flies with pan-neural (<i>elav</i>::<i>Gal4</i>) expression of indicated TDP-43 variants were assayed for longevity. (B) Median survival of respective survival curves. (C) Cross-comparison of survival curves with regard to statistical significance after Bonferroni correction. (D) Age-dependent locomotion defects after TDP-43 expression in motor neurons. Flies expressing indicated TDP-43 variants specifically in motor neurons (<i>D42::Gal4</i>) were assayed for negative geotaxis at 1, 10 and 20 days post eclosion. (E) Detailed summary of statistical analysis (2-Way ANOVA followed by Bonferroni post-hoc tests) of age-dependent locomotion effects. Genotypes of flies analyzed: <i>elav^C155::Gal4/Y;UAS::TDP-43/+</i> in longevity analysis and <i>w/Y;UAS::TDP-43/+;D42::Gal4/+</i> in case of locomotion assay. <i>elav^C155::Gal4/Y</i> (longevity) and <i>w/Y;;D42::Gal4</i> (climbing) served as controls. *p<0.05; **p<0.01; ***p<0.001; ns not significant.</p>", "links"=>[], "tags"=>["rna-binding", "tdp-43-mediated", "neural", "defects"], "article_id"=>505790, "categories"=>["Neuroscience"], "users"=>["Aaron Voigt", "David Herholz", "Fabienne C. Fiesel", "Kavita Kaur", "Daniel Müller", "Peter Karsten", "Stephanie S. Weber", "Philipp J. Kahle", "Till Marquardt", "Jörg B. Schulz"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012247.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Requirement_for_RNA_binding_activity_for_TDP_43_mediated_neural_defects_in_Drosophila_/505790", "title"=>"Requirement for RNA-binding activity for TDP-43-mediated neural defects in <i>Drosophila</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-08-18 01:36:30"}
• {"files"=>["https://ndownloader.figshare.com/files/834957"], "description"=>"<p>(A) Schematic overview of TDP-43 variants tested <i>in vivo</i>. Positions and nature of amino acid substitutions and size of two C-terminal fragments (CTFs) analyzed are indicated. Synthetic mutations (SM) were introduced to interfere with TDP-43 localization or function. Mutations in the nuclear localization signal (ΔNLS) were introduced to target TDP-43 to the cytoplasm and mutations F147L/F149L (FFLL) in the first RNA recognition motive (RRM1) were introduced to impair TDP-43 inherent RNA-binding capacity. (B) Loss of RNA-binding by TDP-43^FFLL. Biotinylated oligonucleotides were incubated with lysates from either untransfected HEK293 cells or HEK293 cells transfected with FLAG-tagged TDP-43^WT or TDP-43^FFLL (left, input) followed by UV crosslinking and streptavidin-pulldown of Biotin-RNA (right, pulldown). Precipitates were separated, blotted and membranes probed with FLAG- (upper panel) and TDP-43-specific (lower panel) antibodies to assay co-precipitation of TDP-43. Note: Co-precipitation of endogenous TDP-43 with (UG)₁₂-repeats in all lysates. Ectopic FLAG-TDP-43^WT, but not FLAG-TDP-43^FFLL co-precipitated with cognate UG repeats. GAPDH served as loading control for protein input. (C) Equalized pan-neural expression of <i>φ-C31</i>-inserted TDP-43 variants in adult <i>Drosophilae</i>. TDP-43 expression was visualized using an anti-human TDP-43 antibody. Syntaxin served as loading control. (D) Assessment of relative TBPH and TDP-43 expression levels. Left graph: Relative abundance of endogenous TBPH transcripts in relation to <i>actin5C</i> of wild type strain OregonR (OreR), the Gal4-driver line (<i>elav^C155::Gal4</i>) and flies with pan-neural TDP-43 expression (<i>elav^C155::Gal4/Y;UAS::TDP-43^WT/+</i>). TBPH levels were not significantly different in analyzed genotypes. Right graph: mRNA abundance of TDP-43 in flies with pan-neural expression of the different TDP-43 variants normalized to <i>actin5C</i> and <i>TBPH</i> mRNA levels. Significant differences are indicated. *p<0.05; ***p<0.001. Head lysates of flies with pan-neural expression of TDP-43 were used for Western blot and qPCR analysis. <i>elav::Gal4</i> flies without a TDP-43 transgene (elav) were used as negative control.</p>", "links"=>[], "tags"=>["tdp-43", "variants", "ectopic"], "article_id"=>505321, "categories"=>["Neuroscience"], "users"=>["Aaron Voigt", "David Herholz", "Fabienne C. Fiesel", "Kavita Kaur", "Daniel Müller", "Peter Karsten", "Stephanie S. Weber", "Philipp J. Kahle", "Till Marquardt", "Jörg B. Schulz"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012247.g001", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Analysis_of_different_TDP_43_variants_used_for_ectopic_expression_/505321", "title"=>"Analysis of different TDP-43 variants used for ectopic expression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-08-18 01:28:41"}
• {"files"=>["https://ndownloader.figshare.com/files/415952", "https://ndownloader.figshare.com/files/415990", "https://ndownloader.figshare.com/files/416028", "https://ndownloader.figshare.com/files/416050", "https://ndownloader.figshare.com/files/416073"], "description"=>"<div><p>Alteration and/or mutations of the ribonucleoprotein TDP-43 have been firmly linked to human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The relative impacts of TDP-43 alteration, mutation, or inherent protein function on neural integrity, however, remain less clear—a situation confounded by conflicting reports based on transient and/or random-insertion transgenic expression. We therefore performed a stringent comparative investigation of impacts of these TDP-43 modifications on neural integrity <em>in vivo</em>. To achieve this, we systematically screened ALS/FTLD-associated and synthetic TDP-43 isoforms via same-site gene insertion and neural expression in <em>Drosophila</em>; followed by transposon-based motor neuron-specific transgenesis in a chick vertebrate system. Using this bi-systemic approach we uncovered a requirement of inherent TDP-43 RNA-binding function—but not ALS/FTLD-linked mutation, mislocalization, or truncation—for TDP-43-mediated neurotoxicity <em>in vivo</em>.</p></div>", "links"=>[], "tags"=>["tdp-43-mediated", "neuron", "requires", "rna-binding"], "article_id"=>142119, "categories"=>["Neuroscience"], "users"=>["Aaron Voigt", "David Herholz", "Fabienne C. Fiesel", "Kavita Kaur", "Daniel Müller", "Peter Karsten", "Stephanie S. Weber", "Philipp J. Kahle", "Till Marquardt", "Jörg B. Schulz"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0012247.s001", "https://dx.doi.org/10.1371/journal.pone.0012247.s002", "https://dx.doi.org/10.1371/journal.pone.0012247.s003", "https://dx.doi.org/10.1371/journal.pone.0012247.s004", "https://dx.doi.org/10.1371/journal.pone.0012247.s005"], "stats"=>{"downloads"=>2, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/TDP_43_Mediated_Neuron_Loss_In_Vivo_Requires_RNA_Binding_Activity/142119", "title"=>"TDP-43-Mediated Neuron Loss <em>In Vivo</em> Requires RNA-Binding Activity", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2010-08-18 00:35:19"}
• {"files"=>["https://ndownloader.figshare.com/files/835676"], "description"=>"<p>Expression of TDP-43:GFP variants using different Gal4-driver lines. Impact of TDP-43 expression on vitality was assayed.</p>", "links"=>[], "tags"=>["neurological disorders", "neurological disorders/cognitive neurology and dementia", "neurological disorders/neurogenetics", "neurological disorders/neuromuscular diseases"], "article_id"=>506030, "categories"=>["Neuroscience"], "users"=>["Aaron Voigt", "David Herholz", "Fabienne C. Fiesel", "Kavita Kaur", "Daniel Müller", "Peter Karsten", "Stephanie S. Weber", "Philipp J. Kahle", "Till Marquardt", "Jörg B. Schulz"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012247.t002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_TDP_43_GFP_variants_/506030", "title"=>"Expression of TDP-43:GFP variants.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2010-08-18 01:40:30"}
• {"files"=>["https://ndownloader.figshare.com/files/835062"], "description"=>"<p>HEK293E cells transfected with N-terminal Flag-tagged TDP-43 variants detected with Flag- (left, green) and TDP-43 (middle, red) specific antibodies. Overlay (right) with Hoechst stained DNA (blue). (A) Exogenous TDP-43 had to be visualized via fused Flag-tag, as HEK cells show robust endogenous expression of TDP-43. (B) Ectopic TDP-43^WT mainly localized to the nucleus. (C) In contrast, TDP-43^ΔNLS exclusively localized to cytosol without showing nuclear Flag-signal. Similar to TDP-43^FFLL (D), also TDP-43^MS (E–I) displayed a nuclear localization. However, TDP-43^FFLL localized in a characteristic punctuate pattern throughout the nucleus (D). (J) TDP-43^CTF displayed a predominantly cytoplasmic localization similar to TDP-43^ΔNLS (compare C and J). Scale bar indicates 10 µm.</p>", "links"=>[], "tags"=>["tdp-43", "variants"], "article_id"=>505423, "categories"=>["Neuroscience"], "users"=>["Aaron Voigt", "David Herholz", "Fabienne C. Fiesel", "Kavita Kaur", "Daniel Müller", "Peter Karsten", "Stephanie S. Weber", "Philipp J. Kahle", "Till Marquardt", "Jörg B. Schulz"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012247.g002", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Localization_of_TDP_43_variants_in_human_cells_/505423", "title"=>"Localization of TDP-43 variants in human cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-08-18 01:30:23"}
• {"files"=>["https://ndownloader.figshare.com/files/835249"], "description"=>"<p>Confocal sections of eye imaginal discs from <i>Drosophila</i> larvae (left panel) and motor neurons from <i>Gallus</i> (right panel) expressing indicated TDP-43 variants. To be able to discriminate between the two <i>in vivo</i> systems, ectopic TDP-43 in <i>Drosophila</i> is shown in green, whereas TDP-43 in <i>Gallus</i> is shown in red. Subcellular localization of the different TDP-43 variants was found to be identical between fly and chick. TDP-43^WT (A) localized mainly to the nucleus, while TDP-43^ΔNLS (B) was found predominantly in the cytoplasm. TDP-43^FFLL (C) and TDP-43^A315T (D) displayed a nuclear distribution. Only cells with very high expression levels of usually nuclear TDP-43 displayed a detectable cytoplasmic staining (example in case of TDP-43^FFLL marked by asterisk). DNA was stained with Sytox® Orange (fly, red) or DAPI (chick, white). Scale bar indicates 50 µm. Neuronal expression was mediated by <i>elav::Gal4</i> (flies) or <i>Hb9::Cre</i> (chick).</p>", "links"=>[], "tags"=>["tdp-43"], "article_id"=>505614, "categories"=>["Neuroscience"], "users"=>["Aaron Voigt", "David Herholz", "Fabienne C. Fiesel", "Kavita Kaur", "Daniel Müller", "Peter Karsten", "Stephanie S. Weber", "Philipp J. Kahle", "Till Marquardt", "Jörg B. Schulz"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012247.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Localization_of_TDP_43_in_Drosophila_melanogaster_and_Gallus_gallus_/505614", "title"=>"Localization of TDP-43 in <i>Drosophila melanogaster</i> and <i>Gallus gallus</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-08-18 01:33:34"}
• {"files"=>["https://ndownloader.figshare.com/files/835557"], "description"=>"<p>(A) Stable unilateral expression of human TDP-43 variants in chick (<i>Gallus gallus</i>) spinal cord. [i] Schematic of expression system mediating motor neuron-restricted expression upon unilateral transfection. [ii] Unilateral expression of human TDP-43^FFLL (red) in embryonic day 9 (E9) chick spinal cord (nuclei labeled with DAPI: blue): transversal section at lumbar levels. “−” and “+” respectively indicate control and transfected hemicords. Isl1/2 labels motor neuron nuclei (green). (B) [i] Examples of thoracic motor columns (Isl1/2⁺ motor neurons: green) upon TDP-43 variant expression (red). [ii] Quantification of motor neuron loss upon TDP-43 variant expression over all obtained sections (in “-” versus “+” hemicord). Differences relative to control (t-student's test) are indicated. (C) [i] Activated Caspase-3 (green) detected in E5 motor neurons upon TDP-43^WT expression (indicated by <i>IRES-cherry</i> bi-cistronic reporter: red). Compared to E5 motor neurons expressing TDP-43^WT, little activation of Caspase-3 was detected upon TDP-43^CTF expression. [ii] Quantification of Caspase-3 activation in motor neurons of transfected hemicords versus vector control. Significant differences are indicated (t-student's test - relative to control). *p<0.05; **p<0.01; ***p<0.001; ns not significant.</p>", "links"=>[], "tags"=>["tdp-43-mediated", "neuron"], "article_id"=>505916, "categories"=>["Neuroscience"], "users"=>["Aaron Voigt", "David Herholz", "Fabienne C. Fiesel", "Kavita Kaur", "Daniel Müller", "Peter Karsten", "Stephanie S. Weber", "Philipp J. Kahle", "Till Marquardt", "Jörg B. Schulz"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012247.g005", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_RNA_binding_activity_is_required_for_TDP_43_mediated_motor_neuron_loss_in_chick_/505916", "title"=>"RNA-binding activity is required for TDP-43-mediated motor neuron loss in chick.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-08-18 01:38:36"}
• {"files"=>["https://ndownloader.figshare.com/files/835710"], "description"=>"<p>Expression of TDP-43 variants using different Gal4-driver lines. Impact of TDP-43 expression on vitality was assayed.</p>", "links"=>[], "tags"=>["tdp-43"], "article_id"=>506073, "categories"=>["Neuroscience"], "users"=>["Aaron Voigt", "David Herholz", "Fabienne C. Fiesel", "Kavita Kaur", "Daniel Müller", "Peter Karsten", "Stephanie S. Weber", "Philipp J. Kahle", "Till Marquardt", "Jörg B. Schulz"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012247.t001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_TDP_43_variants_/506073", "title"=>"Expression of TDP-43 variants.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2010-08-18 01:41:13"}

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F1000Prime