The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies

Abstract

TAR DNA-binding protein 43 (TDP-43) is a highly conserved nuclear RNA/DNA-binding protein involved in the regulation of RNA processing. The accumulation of TDP-43 aggregates in the central nervous system is a common feature of many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Accumulating evidence suggests that prion-like spreading of aberrant protein aggregates composed of tau, amyloid-β, and α-synuclein is involved in the progression of neurodegenerative diseases such as AD and PD. Similar to those of prion-like proteins, pathological aggregates of TDP-43 can be transferred from cell-to-cell in a seed-dependent and self-templating manner. Here, we review clinical and experimental studies supporting the prion-like spreading of misfolded TDP-43 and discuss the molecular mechanisms underlying the propagation of these pathological aggregated proteins. The idea that misfolded TDP-43 spreads in a prion-like manner between cells may guide novel therapeutic strategies for TDP-43-associated neurodegenerative diseases.

Fig. 1. Schematic representation of the structure and aggregation-associated mutations of TDP-43.

The TDP-43 protein contains a nuclear localization signal (NLS), 2 RNA-recognition motifs (RRM1 and RRM2), a nuclear export sequence (NES), and a glycine-rich region (GRR). Numerous disease-associated TDP-43 mutations have been identified in the GRR. Most disease-associated TDP-43 missense mutations have been identified to accelerate TDP-43 aggregation.

Fig. 2. Schematic overview of misfolded TDP-43 propagation in TDP-43 proteinopathies.

a Proposed mechanism of self-propagation of misfolded TDP-43 in TDP-43 proteinopathies. Misfolded TDP-43 aggregates bind to their normal counterparts and induce the misfolding of bound protein in a template-dependent manner. This process leads to the elongation of misfolded TDP-43 aggregates. Amplification of self-templating amyloid fibrils results from the fragmentation of TDP-43 aggregates, which exposes new ends. b Putative mechanism of cell-to-cell spreading of TDP-43 aggregates. TDP-43 aggregates may propagate via exosomes (release from multivesicular bodies (MVBs)), tunneling nanotubes (TNTs), or synaptic transmission (transport from presynaptic to postsynaptic terminals) from donor cells to acceptor cells. Moreover, glial cells (oligodendrocytes, astrocytes, and microglia) can take up TDP-43 aggregates through phagocytosis, after which misfolded TDP-43 is released from glial cells and transmitted to neurons and neighboring glial cells. The neuron-to-glia or glia-to-neuron transfer of TDP-43 has been observed, but its propagation mechanism is not clear.