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

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.

Keywords: 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.

Fig. 1

TAR DNA‐binding protein structure. Schematic diagram depicting the domain organisation of 414 amino acid long human TDP‐43. TDP‐43 mainly consists of an N‐terminal domain with a nuclear localisation signal (NLS: 82–98), two RNA‐recognition motifs (RRM1: 104–176 and RRM2: 192–262), a nuclear export signal (NES: 239–250) and a C‐terminal region encompassing a hydrophobic patch (HP: 318–343) and glutamine/asparagine‐rich (Q/N:345–366) and glycine‐rich (366–414) regions. Additionally, mitochondrial localisation motifs (M1: 35–41; M3:146–150; M5: 294–300) are also shown. For comparison, a schematic of TDP‐1 (C. elegans TDP‐43 orthologue) is shown. TDP‐1 shows a similar structural architecture in the N‐terminus as human TDP‐43 but lacks the HP and Q/N regions in the C‐terminus. Schematic adapted and modified from Lagier‐Tourenne et al. (2010).