Journal Article (Review Article)

DZNE-2026-00082

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models.

Pir, G. J. ; Buddenkotte, J. ; Alam, M. A. ; Own, A. ; Eck, R. J. ; Kraemer, B. C. ; Mandelkow, E.DZNE* ; Steinhoff, M.

2026
Wiley-Blackwell Oxford [u.a.]

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Please use a persistent id in citations: doi:10.1111/febs.70239

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.

Keyword(s): Animals (MeSH) ; Caenorhabditis elegans: genetics (MeSH) ; Caenorhabditis elegans: metabolism (MeSH) ; TDP-43 Proteinopathies: genetics (MeSH) ; TDP-43 Proteinopathies: pathology (MeSH) ; TDP-43 Proteinopathies: metabolism (MeSH) ; DNA-Binding Proteins: genetics (MeSH) ; DNA-Binding Proteins: metabolism (MeSH) ; DNA-Binding Proteins: chemistry (MeSH) ; Disease Models, Animal (MeSH) ; Humans (MeSH) ; Caenorhabditis elegans Proteins: genetics (MeSH) ; Caenorhabditis elegans Proteins: metabolism (MeSH) ; Neurodegenerative Diseases: genetics (MeSH) ; Neurodegenerative Diseases: pathology (MeSH) ; Neurodegenerative Diseases: metabolism (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Frontotemporal Dementia: genetics (MeSH) ; Frontotemporal Dementia: pathology (MeSH) ; Frontotemporal Dementia: metabolism (MeSH) ; Alzheimer's disease (AD) ; C. elegans ; GABA ; G‐protein coupled receptors ; Huntington's disease ; Parkinson's disease (PD) ; TDP‐43/TDP‐1 ; acetylcholine ; amyotrophic lateral sclerosis (ALS) ; extracellular vesicles (EV) ; frontotemporal dementia (FTD) ; ion channels ; limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) ; proteinopathies ; tau ; DNA-Binding Proteins ; Caenorhabditis elegans Proteins ; TARDBP protein, human

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Contributing Institute(s):

1. Structural Principles of Neurodegeneration (AG (Eckhard) Mandelkow)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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