Characterizing Amyotrophic Lateral Sclerosis progression through Extracellular Vesicles.

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease caused by progressive loss of motor neurons (MNs) without an available cure. Different genes had been associated with the development and progression of ALS, including Hexanuclotide repeat expansion in C9orf72, TAR DNA-binding protein 43 (TDP-43), superoxide dismutase (SOD1) and fused in sarcoma (FUS). Cell-to-cell communication can occur via extracellular vesicles (EVs) which are small vesicles released from all cell types under physiological and pathological conditions. EVs gained particular interest in the study of neurological disorders because they have the capability of spreading pathological targets to the neighboring cells. Here we used induced pluripotent stem cells (iPSCs)-derived MNs and their isolated EVs, from ALS patients, healthy control, and isogenic control lines, to measure the relative ALS-associated protein expression levels in MNs and EVs. We also treated healthy MNs with EVs derived from both ALS and healthy control MNs. First, we will demonstrate the expression of ALS-associated proteins in MNs and EVs. Then, we will show the effect of ALS-EVs on MN morphology, specifically in the number and length of dendrites, apoptosis, and mislocalization of TDP-43. Our results reveal the promising potential of iPSC-derived MNs and their EVs in the propagation of ALS-associated pathophysiology, approaching a comprehensive characterization of ALS and potential therapeutic interventions.