Decoding TDP-43: the molecular chameleon of neurodegenerative diseases
Abstract TAR DNA-binding protein 43 (TDP-43) has emerged as a critical player in neurodegenerative disorders, with its dysfunction implicated in a wide spectrum of diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer’s disease (AD). This com...
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| Format: | Article |
| Language: | English |
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BMC
2024-12-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-024-01914-9 |
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| author | Jixiang Zeng Chunmei Luo Yang Jiang Tao Hu Bixia Lin Yuanfang Xie Jiao Lan Jifei Miao |
| author_facet | Jixiang Zeng Chunmei Luo Yang Jiang Tao Hu Bixia Lin Yuanfang Xie Jiao Lan Jifei Miao |
| author_sort | Jixiang Zeng |
| collection | DOAJ |
| description | Abstract TAR DNA-binding protein 43 (TDP-43) has emerged as a critical player in neurodegenerative disorders, with its dysfunction implicated in a wide spectrum of diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer’s disease (AD). This comprehensive review explores the multifaceted roles of TDP-43 in both physiological and pathological contexts. We delve into TDP-43’s crucial functions in RNA metabolism, including splicing regulation, mRNA stability, and miRNA biogenesis. Particular emphasis is placed on recent discoveries regarding TDP-43’s involvement in DNA interactions and chromatin dynamics, highlighting its broader impact on gene expression and genome stability. The review also examines the complex pathogenesis of TDP-43-related disorders, discussing the protein’s propensity for aggregation, its effects on mitochondrial function, and its non-cell autonomous impacts on glial cells. We provide an in-depth analysis of TDP-43 pathology across various neurodegenerative conditions, from well-established associations in ALS and FTLD to emerging roles in diseases such as Huntington’s disease and Niemann-Pick C disease. The potential of TDP-43 as a therapeutic target is explored, with a focus on recent developments in targeting cryptic exon inclusion and other TDP-43-mediated processes. This review synthesizes current knowledge on TDP-43 biology and pathology, offering insights into the protein’s central role in neurodegeneration and highlighting promising avenues for future research and therapeutic interventions. |
| format | Article |
| id | doaj-art-bf4c0490ee6247c99348062a6ea22876 |
| institution | Kabale University |
| issn | 2051-5960 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-bf4c0490ee6247c99348062a6ea228762025-01-05T12:49:38ZengBMCActa Neuropathologica Communications2051-59602024-12-0112112810.1186/s40478-024-01914-9Decoding TDP-43: the molecular chameleon of neurodegenerative diseasesJixiang Zeng0Chunmei Luo1Yang Jiang2Tao Hu3Bixia Lin4Yuanfang Xie5Jiao Lan6Jifei Miao7Shenzhen Baoan Traditional Chinese Medicine Hospital, Guangzhou University of Chinese MedicineShenzhen Baoan Traditional Chinese Medicine Hospital, Guangzhou University of Chinese MedicineShenzhen Baoan Traditional Chinese Medicine Hospital, Guangzhou University of Chinese MedicineShenzhen Baoan Traditional Chinese Medicine Hospital, Guangzhou University of Chinese MedicineShenzhen Baoan Traditional Chinese Medicine Hospital, Guangzhou University of Chinese MedicineShenzhen Baoan Traditional Chinese Medicine Hospital, Guangzhou University of Chinese MedicineShenzhen Baoan Traditional Chinese Medicine Hospital, Guangzhou University of Chinese MedicineShenzhen Baoan Traditional Chinese Medicine Hospital, Guangzhou University of Chinese MedicineAbstract TAR DNA-binding protein 43 (TDP-43) has emerged as a critical player in neurodegenerative disorders, with its dysfunction implicated in a wide spectrum of diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer’s disease (AD). This comprehensive review explores the multifaceted roles of TDP-43 in both physiological and pathological contexts. We delve into TDP-43’s crucial functions in RNA metabolism, including splicing regulation, mRNA stability, and miRNA biogenesis. Particular emphasis is placed on recent discoveries regarding TDP-43’s involvement in DNA interactions and chromatin dynamics, highlighting its broader impact on gene expression and genome stability. The review also examines the complex pathogenesis of TDP-43-related disorders, discussing the protein’s propensity for aggregation, its effects on mitochondrial function, and its non-cell autonomous impacts on glial cells. We provide an in-depth analysis of TDP-43 pathology across various neurodegenerative conditions, from well-established associations in ALS and FTLD to emerging roles in diseases such as Huntington’s disease and Niemann-Pick C disease. The potential of TDP-43 as a therapeutic target is explored, with a focus on recent developments in targeting cryptic exon inclusion and other TDP-43-mediated processes. This review synthesizes current knowledge on TDP-43 biology and pathology, offering insights into the protein’s central role in neurodegeneration and highlighting promising avenues for future research and therapeutic interventions.https://doi.org/10.1186/s40478-024-01914-9TDP-43neurodegenerationRNA metabolismchromatin regulationcryptic exonsmitochondrial dysfunction |
| spellingShingle | Jixiang Zeng Chunmei Luo Yang Jiang Tao Hu Bixia Lin Yuanfang Xie Jiao Lan Jifei Miao Decoding TDP-43: the molecular chameleon of neurodegenerative diseases Acta Neuropathologica Communications TDP-43 neurodegeneration RNA metabolism chromatin regulation cryptic exons mitochondrial dysfunction |
| title | Decoding TDP-43: the molecular chameleon of neurodegenerative diseases |
| title_full | Decoding TDP-43: the molecular chameleon of neurodegenerative diseases |
| title_fullStr | Decoding TDP-43: the molecular chameleon of neurodegenerative diseases |
| title_full_unstemmed | Decoding TDP-43: the molecular chameleon of neurodegenerative diseases |
| title_short | Decoding TDP-43: the molecular chameleon of neurodegenerative diseases |
| title_sort | decoding tdp 43 the molecular chameleon of neurodegenerative diseases |
| topic | TDP-43 neurodegeneration RNA metabolism chromatin regulation cryptic exons mitochondrial dysfunction |
| url | https://doi.org/10.1186/s40478-024-01914-9 |
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