mTh1 driven expression of hTDP-43 results in typical ALS/FTLD neuropathological symptoms.
Transgenic mouse models are indispensable tools to mimic human diseases and analyze the effectiveness of related new drugs. For a long time amyotrophic lateral sclerosis (ALS) research depended on only a few mouse models that exhibit a very strong and early phenotype, e.g. SOD1 mice, resulting in a...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2018-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5963763?pdf=render |
| _version_ | 1818237873291264000 |
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| author | Barbara Scherz Roland Rabl Stefanie Flunkert Siegfried Rohler Joerg Neddens Nicole Taub Magdalena Temmel Ute Panzenboeck Vera Niederkofler Robert Zimmermann Birgit Hutter-Paier |
| author_facet | Barbara Scherz Roland Rabl Stefanie Flunkert Siegfried Rohler Joerg Neddens Nicole Taub Magdalena Temmel Ute Panzenboeck Vera Niederkofler Robert Zimmermann Birgit Hutter-Paier |
| author_sort | Barbara Scherz |
| collection | DOAJ |
| description | Transgenic mouse models are indispensable tools to mimic human diseases and analyze the effectiveness of related new drugs. For a long time amyotrophic lateral sclerosis (ALS) research depended on only a few mouse models that exhibit a very strong and early phenotype, e.g. SOD1 mice, resulting in a short treatment time window. By now, several models are available that need to be characterized to highlight characteristics of each model. Here we further characterized the mThy1-hTDP-43 transgenic mouse model TAR6/6 that overexpresses wild type human TARDBP, also called TDP-43, under control of the neuronal Thy-1 promoter presented by Wils and colleagues, 2010, by using biochemical, histological and behavioral readouts. Our results show that TAR6/6 mice exhibit a strong TDP-43 expression in the hippocampus, spinal cord, hypothalamus and medulla oblongata. Apart from prominent protein expression in the nucleus, TDP-43 protein was found at lower levels in the cytosol of transgenic mice. Additionally, we detected insoluble TDP-43 in the cortex, motoneuron loss, and increased neuroinflammation in the central nervous system of TAR6/6 animals. Behavioral analyses revealed early motor deficits in the clasping- and wire suspension test as well as decreased anxiety in the elevated plus maze. Further motor tests showed differences at later time points compared to non-transgenic littermates, thus allowing the observation of onset and severity of such deficits. Together, TAR6/6 mice are a valuable tool to test new ALS/FTLD drugs that target TDP-43 expression and insolubility, neuroinflammation, motoneuron loss or other TDP-43 related downstream signaling pathways since these mice exhibit a later pathology as previously used ALS/FTLD mouse models. |
| first_indexed | 2024-12-12T12:32:40Z |
| format | Article |
| id | doaj.art-47f096b395ef46148adcfa7f08e8eb0d |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T12:32:40Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-47f096b395ef46148adcfa7f08e8eb0d2022-12-22T00:24:23ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01135e019767410.1371/journal.pone.0197674mTh1 driven expression of hTDP-43 results in typical ALS/FTLD neuropathological symptoms.Barbara ScherzRoland RablStefanie FlunkertSiegfried RohlerJoerg NeddensNicole TaubMagdalena TemmelUte PanzenboeckVera NiederkoflerRobert ZimmermannBirgit Hutter-PaierTransgenic mouse models are indispensable tools to mimic human diseases and analyze the effectiveness of related new drugs. For a long time amyotrophic lateral sclerosis (ALS) research depended on only a few mouse models that exhibit a very strong and early phenotype, e.g. SOD1 mice, resulting in a short treatment time window. By now, several models are available that need to be characterized to highlight characteristics of each model. Here we further characterized the mThy1-hTDP-43 transgenic mouse model TAR6/6 that overexpresses wild type human TARDBP, also called TDP-43, under control of the neuronal Thy-1 promoter presented by Wils and colleagues, 2010, by using biochemical, histological and behavioral readouts. Our results show that TAR6/6 mice exhibit a strong TDP-43 expression in the hippocampus, spinal cord, hypothalamus and medulla oblongata. Apart from prominent protein expression in the nucleus, TDP-43 protein was found at lower levels in the cytosol of transgenic mice. Additionally, we detected insoluble TDP-43 in the cortex, motoneuron loss, and increased neuroinflammation in the central nervous system of TAR6/6 animals. Behavioral analyses revealed early motor deficits in the clasping- and wire suspension test as well as decreased anxiety in the elevated plus maze. Further motor tests showed differences at later time points compared to non-transgenic littermates, thus allowing the observation of onset and severity of such deficits. Together, TAR6/6 mice are a valuable tool to test new ALS/FTLD drugs that target TDP-43 expression and insolubility, neuroinflammation, motoneuron loss or other TDP-43 related downstream signaling pathways since these mice exhibit a later pathology as previously used ALS/FTLD mouse models.http://europepmc.org/articles/PMC5963763?pdf=render |
| spellingShingle | Barbara Scherz Roland Rabl Stefanie Flunkert Siegfried Rohler Joerg Neddens Nicole Taub Magdalena Temmel Ute Panzenboeck Vera Niederkofler Robert Zimmermann Birgit Hutter-Paier mTh1 driven expression of hTDP-43 results in typical ALS/FTLD neuropathological symptoms. PLoS ONE |
| title | mTh1 driven expression of hTDP-43 results in typical ALS/FTLD neuropathological symptoms. |
| title_full | mTh1 driven expression of hTDP-43 results in typical ALS/FTLD neuropathological symptoms. |
| title_fullStr | mTh1 driven expression of hTDP-43 results in typical ALS/FTLD neuropathological symptoms. |
| title_full_unstemmed | mTh1 driven expression of hTDP-43 results in typical ALS/FTLD neuropathological symptoms. |
| title_short | mTh1 driven expression of hTDP-43 results in typical ALS/FTLD neuropathological symptoms. |
| title_sort | mth1 driven expression of htdp 43 results in typical als ftld neuropathological symptoms |
| url | http://europepmc.org/articles/PMC5963763?pdf=render |
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