TDP-43 mutants with different aggregation properties exhibit distinct toxicity, axonal transport, and secretion for disease progression in a mouse ALS/FTLD model
TDP-43 accumulates and forms inclusions in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) and is assumed to cause neurodegenerative processes. The morphologies and cellular and areal distributions of accumulated TDP-43 inclusions are pathologically divers...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-08-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125002049 |
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| author | Hideki Mori Tokiharu Sato Shintaro Tsuboguchi Masahiko Takahashi Yuka Nakamura Kana Hoshina Taisuke Kato Masahiro Fujii Osamu Onodera Masaki Ueno |
| author_facet | Hideki Mori Tokiharu Sato Shintaro Tsuboguchi Masahiko Takahashi Yuka Nakamura Kana Hoshina Taisuke Kato Masahiro Fujii Osamu Onodera Masaki Ueno |
| author_sort | Hideki Mori |
| collection | DOAJ |
| description | TDP-43 accumulates and forms inclusions in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) and is assumed to cause neurodegenerative processes. The morphologies and cellular and areal distributions of accumulated TDP-43 inclusions are pathologically diverse among ALS/FTLD patients; however, whether and how different types of TDP-43 affect the process and severity of disease progression are not fully understood. Here, we compared the pathological events evoked by TDP-43 mutations, which have different aggregation properties, in cultured neurons and the cerebral cortex in mice. We selected TDP-43C173/175S and TDP-43G298S as aggregation-prone and nonprone mutants, respectively. Cytoplasmically expressed TDP-43C173/175S induced insoluble inclusions more robustly than TDP-43G298S did. In contrast, TDP-43G298S induced cell death more severely than TDP-43C173/175S. TDP-43G298S was further found to be efficiently transported in axons and led to axon degeneration, while this effect was not obvious in TDP-43C173/175S. Instead, TDP-43C173/175S was frequently trapped in the axon initial segments. Finally, TDP-43G298S was secreted in exosomes and transferred to oligodendrocyte-lineage cells in vitro more efficiently than TDP-43C173/175S to induce cell death. The transfer further evoked cytokine responses in microglial cells. These data revealed that different aggregation properties of TDP-43 cause distinct pathological events. These findings may explain the differences in the neurodegenerative progression and distribution observed among patients with ALS and FTLD. |
| format | Article |
| id | doaj-art-eab14ebd0add4736b8ce426b4c65b8b6 |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-eab14ebd0add4736b8ce426b4c65b8b62025-08-20T03:46:46ZengElsevierNeurobiology of Disease1095-953X2025-08-0121210698810.1016/j.nbd.2025.106988TDP-43 mutants with different aggregation properties exhibit distinct toxicity, axonal transport, and secretion for disease progression in a mouse ALS/FTLD modelHideki Mori0Tokiharu Sato1Shintaro Tsuboguchi2Masahiko Takahashi3Yuka Nakamura4Kana Hoshina5Taisuke Kato6Masahiro Fujii7Osamu Onodera8Masaki Ueno9Department of Neurology, Brain Research Institute, Niigata University, Niigata, Niigata 951-8585, JapanDepartment of System Pathology for Neurological Disorders, Brain Research Institute, Niigata University, Niigata, Niigata 951-8585, JapanDepartment of Neurology, Brain Research Institute, Niigata University, Niigata, Niigata 951-8585, JapanDivision of Virology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata 951-8585, JapanDepartment of System Pathology for Neurological Disorders, Brain Research Institute, Niigata University, Niigata, Niigata 951-8585, JapanDepartment of Molecular Neuroscience, Brain Research Institute, Niigata University, Niigata, Niigata 951-8585, JapanDepartment of Molecular Neuroscience, Brain Research Institute, Niigata University, Niigata, Niigata 951-8585, JapanDivision of Virology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata 951-8585, JapanDepartment of Neurology, Brain Research Institute, Niigata University, Niigata, Niigata 951-8585, Japan; Department of Molecular Neuroscience, Brain Research Institute, Niigata University, Niigata, Niigata 951-8585, Japan; Corresponding author at: Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, Niigata 951-8585, Japan.Department of System Pathology for Neurological Disorders, Brain Research Institute, Niigata University, Niigata, Niigata 951-8585, Japan; Corresponding author at: Department of System Pathology for Neurological Disorders, Brain Research Institute, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, Niigata 951-8585, Japan.TDP-43 accumulates and forms inclusions in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) and is assumed to cause neurodegenerative processes. The morphologies and cellular and areal distributions of accumulated TDP-43 inclusions are pathologically diverse among ALS/FTLD patients; however, whether and how different types of TDP-43 affect the process and severity of disease progression are not fully understood. Here, we compared the pathological events evoked by TDP-43 mutations, which have different aggregation properties, in cultured neurons and the cerebral cortex in mice. We selected TDP-43C173/175S and TDP-43G298S as aggregation-prone and nonprone mutants, respectively. Cytoplasmically expressed TDP-43C173/175S induced insoluble inclusions more robustly than TDP-43G298S did. In contrast, TDP-43G298S induced cell death more severely than TDP-43C173/175S. TDP-43G298S was further found to be efficiently transported in axons and led to axon degeneration, while this effect was not obvious in TDP-43C173/175S. Instead, TDP-43C173/175S was frequently trapped in the axon initial segments. Finally, TDP-43G298S was secreted in exosomes and transferred to oligodendrocyte-lineage cells in vitro more efficiently than TDP-43C173/175S to induce cell death. The transfer further evoked cytokine responses in microglial cells. These data revealed that different aggregation properties of TDP-43 cause distinct pathological events. These findings may explain the differences in the neurodegenerative progression and distribution observed among patients with ALS and FTLD.http://www.sciencedirect.com/science/article/pii/S0969996125002049Axon initial segment (AIS)CallosalCorticospinalLayer VSensorimotor cortexSpreading |
| spellingShingle | Hideki Mori Tokiharu Sato Shintaro Tsuboguchi Masahiko Takahashi Yuka Nakamura Kana Hoshina Taisuke Kato Masahiro Fujii Osamu Onodera Masaki Ueno TDP-43 mutants with different aggregation properties exhibit distinct toxicity, axonal transport, and secretion for disease progression in a mouse ALS/FTLD model Neurobiology of Disease Axon initial segment (AIS) Callosal Corticospinal Layer V Sensorimotor cortex Spreading |
| title | TDP-43 mutants with different aggregation properties exhibit distinct toxicity, axonal transport, and secretion for disease progression in a mouse ALS/FTLD model |
| title_full | TDP-43 mutants with different aggregation properties exhibit distinct toxicity, axonal transport, and secretion for disease progression in a mouse ALS/FTLD model |
| title_fullStr | TDP-43 mutants with different aggregation properties exhibit distinct toxicity, axonal transport, and secretion for disease progression in a mouse ALS/FTLD model |
| title_full_unstemmed | TDP-43 mutants with different aggregation properties exhibit distinct toxicity, axonal transport, and secretion for disease progression in a mouse ALS/FTLD model |
| title_short | TDP-43 mutants with different aggregation properties exhibit distinct toxicity, axonal transport, and secretion for disease progression in a mouse ALS/FTLD model |
| title_sort | tdp 43 mutants with different aggregation properties exhibit distinct toxicity axonal transport and secretion for disease progression in a mouse als ftld model |
| topic | Axon initial segment (AIS) Callosal Corticospinal Layer V Sensorimotor cortex Spreading |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125002049 |
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