Extracellular vesicles in TDP-43 proteinopathies: pathogenesis and biomarker potential

Abstract

Extracellular vesicles (EVs) are membrane-enclosed nanoparticles released by most cell types, and from multiple sub-cellular compartments. They carry a range of cargo biomolecules, including protein and RNA that reflect the type and status of their cell of origin. EVs are associated with the 43 kDa trans-active response DNA binding protein (TDP-43), aggregates of which are a key pathological feature across the spectrum of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other TDP-43 proteinopathies. The secretion of TDP-43 via EVs may have beneficial effects through the cellular clearance of aggregated protein, or detrimental effects via the intercellular spread of templated TDP-43 aggregation. This review examines evidence for the association of TDP-43 with EVs in post mortem tissue, in vitro models and human biofluids, and discusses evidence for EV TDP-43 involvement in pathogenesis via clearance or ‘seeding’ processes. We further discuss the potential for use of EVs in biomarker development, through analysis of TDP-43 or alternative protein and RNA cargoes.

Graphical Abstract:

Fig. 1

Extracellular particle types that can carry protein or RNA in biofluids. Schematic showing an overview of extracellular vesicles (Exosomes, ectosomes, mitovesicles, apoptotic bodies) and non-vesicular particles including High-density lipoprotein (HDL), Low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), chylomicrons, exomeres, supermeres, extracellular ribosomes, vault particles and protein oligomers. Sizes shown are approximate, demonstrating overlapping characteristics between different particle types and the challenge of specific separation. Figure created with BioRender.com

Fig. 2

Potential mechanisms of EV-mediated TDP-43 aggregate formation. EVs can be taken up from the extracellular environment by direct plasma membrane fusion (1) or by a variety of different endocytic processes; clathrin-mediated endocytosis (2), phagocytosis (3), receptor-mediated endocytosis (4), or macropinocytosis (5) resulting in localisation of their TDP-43 cargo to the early endosome. For a seeded aggregation process to occur, TDP-43 must escape the endosome to reach the cytoplasm, possibly via a process of endosomal permeabilization (6). Alternatively, EVs might induce cellular stress signalling (7), resulting in nuclear to cytoplasmic mislocalisation of TDP-43, and a subsequent increase in aggregate formation. Different cell types such as neurons and glia may use different mechanisms of uptake which may influence the fate of the internalised TDP-43. Figure created with BioRender.com