Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice
<p>Abstract</p> <p>Background</p> <p>Abnormal distribution, modification and aggregation of transactivation response DNA-binding protein 43 (TDP-43) are the hallmarks of multiple neurodegenerative diseases, especially frontotemporal lobar degeneration with ubiquitin-pos...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2011-10-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | http://www.molecularneurodegeneration.com/content/6/1/73 |
| _version_ | 1818391408864657408 |
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| author | Dickson Dennis W Stetler Caroline Cao Xiangkun Lin Wen-Lang Zhang Yong-Jie Xu Ya-Fei Lewis Jada Petrucelli Leonard |
| author_facet | Dickson Dennis W Stetler Caroline Cao Xiangkun Lin Wen-Lang Zhang Yong-Jie Xu Ya-Fei Lewis Jada Petrucelli Leonard |
| author_sort | Dickson Dennis W |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Abnormal distribution, modification and aggregation of transactivation response DNA-binding protein 43 (TDP-43) are the hallmarks of multiple neurodegenerative diseases, especially frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Researchers have identified 44 mutations in the <it>TARDBP </it>gene that encode TDP-43 as causative for cases of sporadic and familial ALS <url>http://www.molgen.ua.ac.be/FTDMutations/</url>. Certain mutant forms of TDP-43, such as M337V, are associated with increased low molecular weight (LMW) fragments compared to wild-type (WT) TDP-43 and cause neuronal apoptosis and developmental delay in chick embryos. Such findings support a direct link between altered TDP-43 function and neurodegeneration.</p> <p>Results</p> <p>To explore the pathogenic properties of the M337V mutation, we generated and characterized two mouse lines expressing human TDP-43 (hTDP-43<sub>M337V</sub>) carrying this mutation. hTDP-43<sub>M337V </sub>was expressed primarily in the nuclei of neurons in the brain and spinal cord, and intranuclear and cytoplasmic phosphorylated TDP-43 aggregates were frequently detected. The levels of TDP-43 LMW products of ~25 kDa and ~35 kDa species were also increased in the transgenic mice. Moreover, overexpression of hTDP-43<sub>M337V </sub>dramatically down regulated the levels of mouse TDP-43 (mTDP-43) protein and RNA, indicating TDP-43 levels are tightly controlled in mammalian systems. TDP-43<sub>M337V </sub>mice displayed reactive gliosis, widespread ubiquitination, chromatolysis, gait abnormalities, and early lethality. Abnormal cytoplasmic mitochondrial aggregates and abnormal phosphorylated tau were also detected in the mice.</p> <p>Conclusion</p> <p>Our novel TDP-43<sub>M337V </sub>mouse model indicates that overexpression of hTDP-43<sub>M337V </sub>alone is toxic <it>in vivo</it>. Because overexpression of hTDP-43 in wild-type TDP-43 and TDP-43<sub>M337V </sub>mouse models produces similar phenotypes, the mechanisms causing pathogenesis in the mutant model remain unknown. However, our results suggest that overexpression of the hTDP-43<sub>M337V </sub>can cause neuronal dysfunction due to its effect on a number of cell organelles and proteins, such as mitochondria and TDP-43, that are critical for neuronal activity. The mutant model will serve as a valuable tool in the development of future studies designed to uncover pathways associated with TDP-43 neurotoxicity and the precise roles TDP-43 RNA targets play in neurodegeneration.</p> |
| first_indexed | 2024-12-14T05:13:03Z |
| format | Article |
| id | doaj.art-307a058e264c498f9e652c410c8cddea |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-14T05:13:03Z |
| publishDate | 2011-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-307a058e264c498f9e652c410c8cddea2022-12-21T23:15:54ZengBMCMolecular Neurodegeneration1750-13262011-10-01617310.1186/1750-1326-6-73Expression of mutant TDP-43 induces neuronal dysfunction in transgenic miceDickson Dennis WStetler CarolineCao XiangkunLin Wen-LangZhang Yong-JieXu Ya-FeiLewis JadaPetrucelli Leonard<p>Abstract</p> <p>Background</p> <p>Abnormal distribution, modification and aggregation of transactivation response DNA-binding protein 43 (TDP-43) are the hallmarks of multiple neurodegenerative diseases, especially frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Researchers have identified 44 mutations in the <it>TARDBP </it>gene that encode TDP-43 as causative for cases of sporadic and familial ALS <url>http://www.molgen.ua.ac.be/FTDMutations/</url>. Certain mutant forms of TDP-43, such as M337V, are associated with increased low molecular weight (LMW) fragments compared to wild-type (WT) TDP-43 and cause neuronal apoptosis and developmental delay in chick embryos. Such findings support a direct link between altered TDP-43 function and neurodegeneration.</p> <p>Results</p> <p>To explore the pathogenic properties of the M337V mutation, we generated and characterized two mouse lines expressing human TDP-43 (hTDP-43<sub>M337V</sub>) carrying this mutation. hTDP-43<sub>M337V </sub>was expressed primarily in the nuclei of neurons in the brain and spinal cord, and intranuclear and cytoplasmic phosphorylated TDP-43 aggregates were frequently detected. The levels of TDP-43 LMW products of ~25 kDa and ~35 kDa species were also increased in the transgenic mice. Moreover, overexpression of hTDP-43<sub>M337V </sub>dramatically down regulated the levels of mouse TDP-43 (mTDP-43) protein and RNA, indicating TDP-43 levels are tightly controlled in mammalian systems. TDP-43<sub>M337V </sub>mice displayed reactive gliosis, widespread ubiquitination, chromatolysis, gait abnormalities, and early lethality. Abnormal cytoplasmic mitochondrial aggregates and abnormal phosphorylated tau were also detected in the mice.</p> <p>Conclusion</p> <p>Our novel TDP-43<sub>M337V </sub>mouse model indicates that overexpression of hTDP-43<sub>M337V </sub>alone is toxic <it>in vivo</it>. Because overexpression of hTDP-43 in wild-type TDP-43 and TDP-43<sub>M337V </sub>mouse models produces similar phenotypes, the mechanisms causing pathogenesis in the mutant model remain unknown. However, our results suggest that overexpression of the hTDP-43<sub>M337V </sub>can cause neuronal dysfunction due to its effect on a number of cell organelles and proteins, such as mitochondria and TDP-43, that are critical for neuronal activity. The mutant model will serve as a valuable tool in the development of future studies designed to uncover pathways associated with TDP-43 neurotoxicity and the precise roles TDP-43 RNA targets play in neurodegeneration.</p>http://www.molecularneurodegeneration.com/content/6/1/73aggregationALSmitochondriamouse modeltau |
| spellingShingle | Dickson Dennis W Stetler Caroline Cao Xiangkun Lin Wen-Lang Zhang Yong-Jie Xu Ya-Fei Lewis Jada Petrucelli Leonard Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice Molecular Neurodegeneration aggregation ALS mitochondria mouse model tau |
| title | Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice |
| title_full | Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice |
| title_fullStr | Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice |
| title_full_unstemmed | Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice |
| title_short | Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice |
| title_sort | expression of mutant tdp 43 induces neuronal dysfunction in transgenic mice |
| topic | aggregation ALS mitochondria mouse model tau |
| url | http://www.molecularneurodegeneration.com/content/6/1/73 |
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