Extracellular vesicles and amyotrophic lateral sclerosis: from misfolded protein vehicles to promising clinical biomarkers

Abstract

Extracellular vesicles (EVs) are small reservoirs of different molecules and important mediators of cell-to-cell communication. As putative vehicles of misfolded protein propagation between cells, they have drawn substantial attention in the field of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Moreover, exosome-mediated non-coding RNA delivery may play a crucial role in ALS, given the relevance of RNA homeostasis in disease pathogenesis. Since EVs can enter the systemic circulation and are easily detectable in patients' biological fluids, they have generated broad interest both as diagnostic and prognostic biomarkers and as valuable tools in understanding disease pathogenesis. Here, after a brief introduction on biogenesis and functions of EVs, we aim to investigate their role in neurodegenerative disorders, especially ALS. Specifically, we focus on the main findings supporting EV-mediated protein and RNA transmission in ALS in vitro and in vivo models. Then, we provide an overview of clinical applications of EVs, summarizing the most relevant studies able to detect EVs in blood and cerebrospinal fluid (CSF) of ALS patients, underlying their potential use in aiding diagnosis and prognosis. Finally, we explore the therapeutic applications of EVs in ALS, either as targets or as vehicles of proteins, nucleic acids and molecular drugs.

Keywords: Amyotrophic lateral sclerosis; Biomarkers; Extracellular vesicles; Neurodegenerative disorders; Prion-like properties; Therapeutics.

Fig. 1

Extracellular vesicle cell transmission and their clinical applications in amyotrophic lateral sclerosis. Extracellular vesicles (EVs) mediate cell-to-cell transmission of misfolded proteins (e.g. SOD1, TDP-43 and FUS) in the central nervous system (CNS). EVs can be detectable in blood and cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) affected patients, providing diagnostic and prognostic biomarkers. After their purification from patients’ biofluids, EVs may be manipulated to accommodate proteins, non-coding RNAs or drugs, and subsequently transferred back to the same patients, serving as therapeutic vehicles