%0 Journal Article
%A Pir, Ghulam Jeelani
%A Buddenkotte, Joerg
%A Alam, Majid Ali
%A Own, Ahmed
%A Eck, Randall J
%A Kraemer, Brian C
%A Mandelkow, Eckhard
%A Steinhoff, Martin
%T TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models.
%J The FEBS journal
%V 293
%N 2
%@ 0014-2956
%C Oxford [u.a.]
%I Wiley-Blackwell
%M DZNE-2026-00082
%P 348 - 384
%D 2026
%X 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.
%K Animals
%K Caenorhabditis elegans: genetics
%K Caenorhabditis elegans: metabolism
%K TDP-43 Proteinopathies: genetics
%K TDP-43 Proteinopathies: pathology
%K TDP-43 Proteinopathies: metabolism
%K DNA-Binding Proteins: genetics
%K DNA-Binding Proteins: metabolism
%K DNA-Binding Proteins: chemistry
%K Disease Models, Animal
%K Humans
%K Caenorhabditis elegans Proteins: genetics
%K Caenorhabditis elegans Proteins: metabolism
%K Neurodegenerative Diseases: genetics
%K Neurodegenerative Diseases: pathology
%K Neurodegenerative Diseases: metabolism
%K Amyotrophic Lateral Sclerosis: genetics
%K Amyotrophic Lateral Sclerosis: pathology
%K Amyotrophic Lateral Sclerosis: metabolism
%K Frontotemporal Dementia: genetics
%K Frontotemporal Dementia: pathology
%K Frontotemporal Dementia: metabolism
%K Alzheimer's disease (AD) (Other)
%K C. elegans (Other)
%K GABA (Other)
%K G‐protein coupled receptors (Other)
%K Huntington's disease (Other)
%K Parkinson's disease (PD) (Other)
%K TDP‐43/TDP‐1 (Other)
%K acetylcholine (Other)
%K amyotrophic lateral sclerosis (ALS) (Other)
%K extracellular vesicles (EV) (Other)
%K frontotemporal dementia (FTD) (Other)
%K ion channels (Other)
%K limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) (Other)
%K proteinopathies (Other)
%K tau (Other)
%K DNA-Binding Proteins (NLM Chemicals)
%K Caenorhabditis elegans Proteins (NLM Chemicals)
%K TARDBP protein, human (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40891506
%R 10.1111/febs.70239
%U https://pub.dzne.de/record/284047