Toxic extracellular vesicles (Exosomes) in Amyotrophic Lateral Sclerosis (ALS-EVs)

Toxic extracellular vesicles (EVs), specifically exosomes, are increasingly recognized as critical mediators in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS) and its associated systemic metabolic dysfunction. These vesicles originate in the central nervous system and carry pathogenic cargo, including misfolded proteins like TDP-43, SOD1, and FUS, as well as specific microRNAs and lipids, which they transport to peripheral tissues. In the periphery, these toxic exosomes contribute to hypermetabolism, muscle wasting, and impaired glucose and lipid metabolism, effectively linking neurodegeneration with systemic metabolic collapse. (Basso & Bonetto, 2016, Frontiers in Neuroscience; More et al., 2022, Journal of Extracellular Vesicles). Therapeutic strategies targeting these exosomes focus on inhibiting their biogenesis and secretion using small molecules like GW4869, which targets neutral sphingomyelinase 2 (nSMase2), or by neutralizing the toxic cargo within the circulation. While primarily studied for their role in spreading proteotoxicity between neurons, their impact on the metabolic health of ALS patients represents a significant non-motor therapeutic target. Monitoring exosomal content, particularly TDP-43 and specific miRNAs, serves as a promising biomarker strategy for disease progression and metabolic status. (Iguchi et al., 2016, Brain; StatPearls, ALS, 2023).

Other names

ALS-derived exosomesPathogenic extracellular vesiclesTDP-43-containing exosomesToxic exosomes in ALSPro-inflammatory exosomes

Inhibition of neutral sphingomyelinase 2 (nSMase2) to reduce exosome biogenesis; Inhibition of exosome secretion; Neutralization of toxic exosomal cargo; Blockade of exosome uptake by recipient cells.