Prion-like Spreading of Disease in TDP-43 Proteinopathies

Abstract

TDP-43 is a ubiquitous nuclear protein that plays a central role in neurodegenerative disorders collectively known as TDP-43 proteinopathies. Under physiological conditions, TDP-43 is primarily localized to the nucleus, but in its pathological form it aggregates in the cytoplasm, contributing to neuronal death. Given its association with numerous diseases, particularly ALS and FTLD, the mechanisms underlying TDP-43 aggregation and its impact on neuronal function have been extensively investigated. However, little is still known about the spreading of this pathology from cell to cell. Recent research has unveiled the possibility that TDP-43 may possess prion-like properties. Specifically, misfolded TDP-43 aggregates can act as templates inducing conformational changes in native TDP-43 molecules and propagating the misfolded state across neural networks. This review summarizes the mounting and most recent evidence from in vitro and in vivo studies supporting the prion-like hypothesis and its underlying mechanisms. The prion-like behavior of TDP-43 has significant implications for diagnostics and therapeutics. Importantly, emerging strategies such as small molecule inhibitors, immunotherapies, and gene therapies targeting TDP-43 propagation offer promising avenues for developing effective treatments. By elucidating the mechanisms of TDP-43 spreading, we therefore aim to pave the way for novel therapies for TDP-43-related neurodegenerative diseases.

Keywords: ALS; FTLD-TDP; TDP-43; aggregation; cell-to-cell transmission; pathological spreading; prion-like; proteinopathy.

Figure 1

The low-complexity domain of TDP-43. The structural elements of the glycine-rich C-terminal domain (CTD) within the low-complexity domain (LCD) of TDP-43 (amino acids 274–414) are depicted. Detailed structural analyses have identified distinct subdomains within the CTD: two Gly-aromatic-Ser-rich (GaroS) regions (residues 274–317 and 368–414), an amyloidogenic core divided into a hydrophobic region (HR, residues 318–342), and a Q/N-rich region (residues 341–369). The potential phosphorylation sites (S375/379, S403/S404, and S409/S410) that may influence aggregation are also indicated.

Figure 2

Intracellular and extracellular processes leading to the prion-like spread of TDP-43. The interplay between intracellular and extracellular factors that contribute to the prion-like spread of TDP-43 pathology is highlighted. Within cells, TDP-43 can form aggregates in response to cellular stress, undergo fragmentation and structural changes, and become mislocalized to the cytoplasm. Mutations and cleavage events can further exacerbate aggregation. These intracellular processes set the stage for the propagation of TDP-43 pathology. Extracellularly, TDP-43 aggregates can be released into the surrounding environment through exosomes, small vesicles that facilitate intercellular communication. These exosomes can transport TDP-43 aggregates to neighboring cells, potentially spreading the pathology to new regions of the brain or other tissues.