Reference - Detail
| RRC ID | 88065 |
|---|---|
| Author | Pir GJ, Buddenkotte J, Alam MA, Own A, Eck RJ, Kraemer BC, Mandelkow E, Steinhoff M. |
| Title | TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models. |
| Journal | 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. |
| Volume | 293(2) |
| Pages | 348-384 |
| Published | 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 |
| Altmetric score |
オルトメトリクス指標項目
|
| The most frequently cited source | News |
| Total number of mentions | 1 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| C.elegans | tm4439 tm985 |