TDP‐43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models

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.