TY  - JOUR
AU  - Pir, Ghulam Jeelani
AU  - Buddenkotte, Joerg
AU  - Alam, Majid Ali
AU  - Own, Ahmed
AU  - Eck, Randall J
AU  - Kraemer, Brian C
AU  - Mandelkow, Eckhard
AU  - Steinhoff, Martin
TI  - TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models.
JO  - The FEBS journal
VL  - 293
IS  - 2
SN  - 0014-2956
CY  - Oxford [u.a.]
PB  - Wiley-Blackwell
M1  - DZNE-2026-00082
SP  - 348 - 384
PY  - 2026
AB  - 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.
KW  - Animals
KW  - Caenorhabditis elegans: genetics
KW  - Caenorhabditis elegans: metabolism
KW  - TDP-43 Proteinopathies: genetics
KW  - TDP-43 Proteinopathies: pathology
KW  - TDP-43 Proteinopathies: metabolism
KW  - DNA-Binding Proteins: genetics
KW  - DNA-Binding Proteins: metabolism
KW  - DNA-Binding Proteins: chemistry
KW  - Disease Models, Animal
KW  - Humans
KW  - Caenorhabditis elegans Proteins: genetics
KW  - Caenorhabditis elegans Proteins: metabolism
KW  - Neurodegenerative Diseases: genetics
KW  - Neurodegenerative Diseases: pathology
KW  - Neurodegenerative Diseases: metabolism
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: pathology
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Frontotemporal Dementia: genetics
KW  - Frontotemporal Dementia: pathology
KW  - Frontotemporal Dementia: metabolism
KW  - Alzheimer's disease (AD) (Other)
KW  - C. elegans (Other)
KW  - GABA (Other)
KW  - G‐protein coupled receptors (Other)
KW  - Huntington's disease (Other)
KW  - Parkinson's disease (PD) (Other)
KW  - TDP‐43/TDP‐1 (Other)
KW  - acetylcholine (Other)
KW  - amyotrophic lateral sclerosis (ALS) (Other)
KW  - extracellular vesicles (EV) (Other)
KW  - frontotemporal dementia (FTD) (Other)
KW  - ion channels (Other)
KW  - limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) (Other)
KW  - proteinopathies (Other)
KW  - tau (Other)
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - Caenorhabditis elegans Proteins (NLM Chemicals)
KW  - TARDBP protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40891506
DO  - DOI:10.1111/febs.70239
UR  - https://pub.dzne.de/record/284047
ER  -