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.