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005     20260122092457.0
024 7 _ |a 10.1111/febs.70239
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024 7 _ |a 0945-5795
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024 7 _ |a 1432-1033
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024 7 _ |a 1742-464X
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024 7 _ |a 1742-4658
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037 _ _ |a DZNE-2026-00082
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Pir, Ghulam Jeelani
|0 P:(DE-2719)2811957
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245 _ _ |a TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models.
260 _ _ |a Oxford [u.a.]
|c 2026
|b Wiley-Blackwell
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520 _ _ |a 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.
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650 _ 7 |a Alzheimer's disease (AD)
|2 Other
650 _ 7 |a C. elegans
|2 Other
650 _ 7 |a GABA
|2 Other
650 _ 7 |a G‐protein coupled receptors
|2 Other
650 _ 7 |a Huntington's disease
|2 Other
650 _ 7 |a Parkinson's disease (PD)
|2 Other
650 _ 7 |a TDP‐43/TDP‐1
|2 Other
650 _ 7 |a acetylcholine
|2 Other
650 _ 7 |a amyotrophic lateral sclerosis (ALS)
|2 Other
650 _ 7 |a extracellular vesicles (EV)
|2 Other
650 _ 7 |a frontotemporal dementia (FTD)
|2 Other
650 _ 7 |a ion channels
|2 Other
650 _ 7 |a limbic‐predominant age‐related TDP‐43 encephalopathy (LATE)
|2 Other
650 _ 7 |a proteinopathies
|2 Other
650 _ 7 |a tau
|2 Other
650 _ 7 |a DNA-Binding Proteins
|2 NLM Chemicals
650 _ 7 |a Caenorhabditis elegans Proteins
|2 NLM Chemicals
650 _ 7 |a TARDBP protein, human
|2 NLM Chemicals
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Caenorhabditis elegans: genetics
|2 MeSH
650 _ 2 |a Caenorhabditis elegans: metabolism
|2 MeSH
650 _ 2 |a TDP-43 Proteinopathies: genetics
|2 MeSH
650 _ 2 |a TDP-43 Proteinopathies: pathology
|2 MeSH
650 _ 2 |a TDP-43 Proteinopathies: metabolism
|2 MeSH
650 _ 2 |a DNA-Binding Proteins: genetics
|2 MeSH
650 _ 2 |a DNA-Binding Proteins: metabolism
|2 MeSH
650 _ 2 |a DNA-Binding Proteins: chemistry
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Caenorhabditis elegans Proteins: genetics
|2 MeSH
650 _ 2 |a Caenorhabditis elegans Proteins: metabolism
|2 MeSH
650 _ 2 |a Neurodegenerative Diseases: genetics
|2 MeSH
650 _ 2 |a Neurodegenerative Diseases: pathology
|2 MeSH
650 _ 2 |a Neurodegenerative Diseases: metabolism
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: genetics
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: pathology
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: metabolism
|2 MeSH
650 _ 2 |a Frontotemporal Dementia: genetics
|2 MeSH
650 _ 2 |a Frontotemporal Dementia: pathology
|2 MeSH
650 _ 2 |a Frontotemporal Dementia: metabolism
|2 MeSH
700 1 _ |a Buddenkotte, Joerg
|b 1
700 1 _ |a Alam, Majid Ali
|b 2
700 1 _ |a Own, Ahmed
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700 1 _ |a Eck, Randall J
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700 1 _ |a Kraemer, Brian C
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700 1 _ |a Mandelkow, Eckhard
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700 1 _ |a Steinhoff, Martin
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773 _ _ |a 10.1111/febs.70239
|g Vol. 293, no. 2, p. 348 - 384
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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