Release of Motor Neuron Exosomes Containing TDP-43 and mTNF-α Near the Neuromuscular Junction Induces Skeletal Muscle Atrophy and Reduced Contractility in a 3D Human Model of ALS
57 Pages Posted: 21 Apr 2020 Sneak Peek Status: Under ReviewMore...
Amyotrophic lateral sclerosis (ALS) is a spectrum of fatal neurodegenerative diseases altering upper and lower motor neuron (MN) and skeletal muscle (SkM) function. Disrupted communication between MN and SkM is believed to be driven by both inflammatory signaling and accumulation of potentially toxic intracellular protein aggregates of TDP-43 (TAR DNA binding protein 43). Here, we examine early events in ALS using a novel 3D model comparing motor unit function in healthy and ALS (OPTNE478G and TARDBPG298S) human iPSC-derived MN in co-culture with healthy iPSC-SkM. We show that in ALS-MN, OPTN inflammatory signaling through NF-κB drives accumulation of mutant TDP-43 to disrupt neuronal function. ALS-MN can transfer inflammatory mTNF-α and TDP-43 aggregates directly to SkM via axonal transport and induce peri-neuromsucular junction (NMJ) release of CD63-positive exosomes leading to cell death, atrophy, and reduced contractile force in SkM. Importantly, SkM pathogenesis could be improved by increasing ALS-MN autophagy which decreases both accumulation of TDP-43 aggregates and pathogenic exosome release. Our results provide the first mechanistic insight into how MN within the spinal cord can propagate pathologic signals to SkM at anatomically distinct sites through axonally transported exosomes and suggest that enhancing MN autophagy could serve as a viable intervention in early ALS.
Keywords: Neuromuscular, Amyotrophic Lateral Sclerosis, muscle atrophy, exosome, TDP-43, organ-on-a-chip, microfluidic device
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