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@ARTICLE{Pir:284047,
      author       = {Pir, Ghulam Jeelani and Buddenkotte, Joerg and Alam, Majid
                      Ali and Own, Ahmed and Eck, Randall J and Kraemer, Brian C
                      and Mandelkow, Eckhard and Steinhoff, Martin},
      title        = {{TDP}-43 proteinopathies and neurodegeneration: insights
                      from {C}aenorhabditis elegans models.},
      journal      = {The FEBS journal},
      volume       = {293},
      number       = {2},
      issn         = {0014-2956},
      address      = {Oxford [u.a.]},
      publisher    = {Wiley-Blackwell},
      reportid     = {DZNE-2026-00082},
      pages        = {348 - 384},
      year         = {2026},
      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.},
      subtyp        = {Review Article},
      keywords     = {Animals / Caenorhabditis elegans: genetics / Caenorhabditis
                      elegans: metabolism / TDP-43 Proteinopathies: genetics /
                      TDP-43 Proteinopathies: pathology / TDP-43 Proteinopathies:
                      metabolism / DNA-Binding Proteins: genetics / DNA-Binding
                      Proteins: metabolism / DNA-Binding Proteins: chemistry /
                      Disease Models, Animal / Humans / Caenorhabditis elegans
                      Proteins: genetics / Caenorhabditis elegans Proteins:
                      metabolism / Neurodegenerative Diseases: genetics /
                      Neurodegenerative Diseases: pathology / Neurodegenerative
                      Diseases: metabolism / Amyotrophic Lateral Sclerosis:
                      genetics / Amyotrophic Lateral Sclerosis: pathology /
                      Amyotrophic Lateral Sclerosis: metabolism / Frontotemporal
                      Dementia: genetics / Frontotemporal Dementia: pathology /
                      Frontotemporal Dementia: metabolism / Alzheimer's disease
                      (AD) (Other) / C. elegans (Other) / GABA (Other) /
                      G‐protein coupled receptors (Other) / Huntington's disease
                      (Other) / Parkinson's disease (PD) (Other) /
                      TDP‐43/TDP‐1 (Other) / acetylcholine (Other) /
                      amyotrophic lateral sclerosis (ALS) (Other) / extracellular
                      vesicles (EV) (Other) / frontotemporal dementia (FTD)
                      (Other) / ion channels (Other) / limbic‐predominant
                      age‐related TDP‐43 encephalopathy (LATE) (Other) /
                      proteinopathies (Other) / tau (Other) / DNA-Binding Proteins
                      (NLM Chemicals) / Caenorhabditis elegans Proteins (NLM
                      Chemicals) / TARDBP protein, human (NLM Chemicals)},
      cin          = {AG (Eckhard) Mandelkow},
      ddc          = {610},
      cid          = {I:(DE-2719)1013014},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40891506},
      doi          = {10.1111/febs.70239},
      url          = {https://pub.dzne.de/record/284047},
}