論文 - 詳細
| RRC ID | 88065 |
|---|---|
| 著者 | Pir GJ, Buddenkotte J, Alam MA, Own A, Eck RJ, Kraemer BC, Mandelkow E, Steinhoff M. |
| タイトル | TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models. |
| ジャーナル | FEBS J |
| Abstract |
TDP-linked proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE), are characterised by pathogenic deposits containing transactive response DNA-binding protein 43 (TDP-43) in the brain and spinal cord of patients. These hallmark pathological features are associated with widespread neuronal dysfunction and progressive neurodegeneration. TDP-43's role as an essential RNA/DNA-binding protein in RNA metabolism and gene expression regulation is clear, but deciphering the intricate pathophysiological mechanisms underpinning TDP-43-mediated neurodegeneration is paramount for developing effective therapies and novel diagnostic tools for early detection before frank neuronal loss occurs. The nematode Caenorhabditis elegans, with highly conserved TDP-43 orthologue TDP-1, serves as a powerful genetic model to investigate the molecular underpinnings of TDP-43 proteinopathies. Here, we provide a brief overview of the structural and functional characteristics of TDP-43 and TDP-1, highlighting their conserved roles in RNA metabolism, stress responses, and neurodegeneration. We then delve into the pathobiology of TDP-43, drawing insights from C. elegans models expressing either monogenic TDP-43 variants or bigenic combinations with ALS-associated risk genes, and discuss how these models have advanced our understanding of the pathomechanisms of TDP-43 proteinopathies. By employing its simplicity and genetic manipulability, we discuss how these models have helped identify chemical and genetic suppressors of TDP-43-induced phenotypes, including small molecules like Pimozide and the probiotic Lacticaseibacillus rhamnosus HA-114, now in clinical trials. This review underscores the translational value of C. elegans in unraveling the biochemical pathways and interactions in TDP-43 proteinopathies that perturb cellular physiology, potentially facilitating mechanism-based therapy development. |
| 巻・号 | 293(2) |
| ページ | 348-384 |
| 公開日 | 2026-1-1 |
| DOI | 10.1111/febs.70239 |
| PMID | 40891506 |
| PMC | PMC12820612 |
| MeSH | Amyotrophic Lateral Sclerosis / genetics Amyotrophic Lateral Sclerosis / metabolism Amyotrophic Lateral Sclerosis / pathology Animals Caenorhabditis elegans* / genetics Caenorhabditis elegans* / metabolism Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / metabolism DNA-Binding Proteins* / chemistry DNA-Binding Proteins* / genetics DNA-Binding Proteins* / metabolism Disease Models, Animal Frontotemporal Dementia / genetics Frontotemporal Dementia / metabolism Frontotemporal Dementia / pathology Humans Neurodegenerative Diseases* / genetics Neurodegenerative Diseases* / metabolism Neurodegenerative Diseases* / pathology TDP-43 Proteinopathies* / genetics TDP-43 Proteinopathies* / metabolism TDP-43 Proteinopathies* / pathology |
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| 最多言及媒体 | News |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 線虫 | tm4439 tm985 |