Spreading of TDP-43 pathology via pyramidal tract induces ALS-like phenotypes in TDP-43 transgenic mice
Abstract Transactive response DNA-binding protein 43 kDa (TDP-43) has been identified as the major component of ubiquitinated inclusions found in patients with sporadic amyotrophic lateral sclerosis (ALS). Increasing evidence suggests prion-like transmission of TDP-43 aggregates via neuroanatomic co...
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| Format: | Article |
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BMC
2021-01-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-020-01112-3 |
| _version_ | 1818963626867818496 |
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| author | Xuebing Ding Zhi Xiang Chi Qin Yongkang Chen Haiyan Tian Lin Meng Danhao Xia Han Liu Jia Song Jun Fu Mingming Ma Xuejing Wang |
| author_facet | Xuebing Ding Zhi Xiang Chi Qin Yongkang Chen Haiyan Tian Lin Meng Danhao Xia Han Liu Jia Song Jun Fu Mingming Ma Xuejing Wang |
| author_sort | Xuebing Ding |
| collection | DOAJ |
| description | Abstract Transactive response DNA-binding protein 43 kDa (TDP-43) has been identified as the major component of ubiquitinated inclusions found in patients with sporadic amyotrophic lateral sclerosis (ALS). Increasing evidence suggests prion-like transmission of TDP-43 aggregates via neuroanatomic connection in vitro and pyramidal tract in vivo. However, it is still unknown whether the spreading of pathological TDP-43 sequentially via pyramidal tract can initiate ALS-like pathology and phenotypes. In this study, we reported that injection of TDP-43 preformed fibrils (PFFs) into the primary motor cortex (M1) of Thy1-e (IRES-TARDBP) 1 mice induced the spreading of pathological TDP-43 along pyramidal tract axons anterogradely. Moreover, TDP-43 PFFs-injected Thy1-e (IRES-TARDBP) 1 mice displayed ALS-like neuropathological features and symptoms, including motor dysfunctions and electrophysiological abnormalities. These findings provide direct evidence that transmission of pathological TDP-43 along pyramidal tract induces ALS-like phenotypes, which further suggest the potential mechanism for TDP-43 proteinopathy. |
| first_indexed | 2024-12-20T12:48:13Z |
| format | Article |
| id | doaj.art-1fe2ee633016431db2d3e3222f11808a |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-20T12:48:13Z |
| publishDate | 2021-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-1fe2ee633016431db2d3e3222f11808a2022-12-21T19:40:14ZengBMCActa Neuropathologica Communications2051-59602021-01-019111710.1186/s40478-020-01112-3Spreading of TDP-43 pathology via pyramidal tract induces ALS-like phenotypes in TDP-43 transgenic miceXuebing Ding0Zhi Xiang1Chi Qin2Yongkang Chen3Haiyan Tian4Lin Meng5Danhao Xia6Han Liu7Jia Song8Jun Fu9Mingming Ma10Xuejing Wang11Department of Neurology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Neurology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Neurology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Neurology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Neurology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Neurology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Neurology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Neurology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Neurology, Affiliated People’s Hospital of Zhengzhou University, Henan Provincial People’s HospitalDepartment of Neurology, Affiliated People’s Hospital of Zhengzhou University, Henan Provincial People’s HospitalDepartment of Neurology, Affiliated People’s Hospital of Zhengzhou University, Henan Provincial People’s HospitalDepartment of Neurology, The First Affiliated Hospital of Zhengzhou UniversityAbstract Transactive response DNA-binding protein 43 kDa (TDP-43) has been identified as the major component of ubiquitinated inclusions found in patients with sporadic amyotrophic lateral sclerosis (ALS). Increasing evidence suggests prion-like transmission of TDP-43 aggregates via neuroanatomic connection in vitro and pyramidal tract in vivo. However, it is still unknown whether the spreading of pathological TDP-43 sequentially via pyramidal tract can initiate ALS-like pathology and phenotypes. In this study, we reported that injection of TDP-43 preformed fibrils (PFFs) into the primary motor cortex (M1) of Thy1-e (IRES-TARDBP) 1 mice induced the spreading of pathological TDP-43 along pyramidal tract axons anterogradely. Moreover, TDP-43 PFFs-injected Thy1-e (IRES-TARDBP) 1 mice displayed ALS-like neuropathological features and symptoms, including motor dysfunctions and electrophysiological abnormalities. These findings provide direct evidence that transmission of pathological TDP-43 along pyramidal tract induces ALS-like phenotypes, which further suggest the potential mechanism for TDP-43 proteinopathy.https://doi.org/10.1186/s40478-020-01112-3Amyotrophic lateral sclerosisTransactive response DNA-binding protein 43 kDaPyramidal tractPreformed fibrilsPrion-like transmission |
| spellingShingle | Xuebing Ding Zhi Xiang Chi Qin Yongkang Chen Haiyan Tian Lin Meng Danhao Xia Han Liu Jia Song Jun Fu Mingming Ma Xuejing Wang Spreading of TDP-43 pathology via pyramidal tract induces ALS-like phenotypes in TDP-43 transgenic mice Acta Neuropathologica Communications Amyotrophic lateral sclerosis Transactive response DNA-binding protein 43 kDa Pyramidal tract Preformed fibrils Prion-like transmission |
| title | Spreading of TDP-43 pathology via pyramidal tract induces ALS-like phenotypes in TDP-43 transgenic mice |
| title_full | Spreading of TDP-43 pathology via pyramidal tract induces ALS-like phenotypes in TDP-43 transgenic mice |
| title_fullStr | Spreading of TDP-43 pathology via pyramidal tract induces ALS-like phenotypes in TDP-43 transgenic mice |
| title_full_unstemmed | Spreading of TDP-43 pathology via pyramidal tract induces ALS-like phenotypes in TDP-43 transgenic mice |
| title_short | Spreading of TDP-43 pathology via pyramidal tract induces ALS-like phenotypes in TDP-43 transgenic mice |
| title_sort | spreading of tdp 43 pathology via pyramidal tract induces als like phenotypes in tdp 43 transgenic mice |
| topic | Amyotrophic lateral sclerosis Transactive response DNA-binding protein 43 kDa Pyramidal tract Preformed fibrils Prion-like transmission |
| url | https://doi.org/10.1186/s40478-020-01112-3 |
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