Extracellular Vesicles in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disease and is the most common adult motor neuron disease. The disease pathogenesis is complex with the perturbation of multiple pathways proposed, including mitochondrial dysfunction, RNA processing, glutamate excitotoxicity, endoplasmic reticulum stress, protein homeostasis and endosomal transport/extracellular vesicle (EV) secretion. EVs are nanoscopic membrane-bound particles that are released from cells, involved in the intercellular communication of proteins, lipids and genetic material, and there is increasing evidence of their role in ALS. After discussing the biogenesis of EVs, we review their roles in the propagation of pathological proteins in ALS, such as TDP-43, SOD1 and FUS, and their contribution to disease pathology. We also discuss the ALS related genes which are involved in EV formation and vesicular trafficking, before considering the EV protein and RNA dysregulation found in ALS and how these have been investigated as potential biomarkers. Finally, we highlight the potential use of EVs as therapeutic agents in ALS, in particular EVs derived from mesenchymal stem cells and EVs as drug delivery vectors for potential treatment strategies.

Attenuation of amyotrophic lateral sclerosis via stem cell and extracellular vesicle therapy: An updated review

“…42 Laboratories are investigating various tactics: including but not limited to (1) what cell to derive the EVs from, often stem cells, but also recent research utilized regulatory T cells, 39 and (2) what vesicle content can be of therapeutic potential, such as proteins, or miRNAs to inhibit relevant inflammatory pathways 41,42 via both reactive astrocytes and activated microglia. 59,60 Ultimately, EVs likely mitigate ALS pathology through broad impacts on antioxidant and antiapoptotic pathways. Despite the therapeutic potential of EVs, the prion-like propagation of pathological contents such as SOD1 and TDP-43 must be considered.…”

“…Astrocytes have also been observed to assume a pathological phenotype in the setting of ALS models; this conversion was ameliorated by EVs 42 . Laboratories are investigating various tactics: including but not limited to (1) what cell to derive the EVs from, often stem cells, but also recent research utilized regulatory T cells, 39 and (2) what vesicle content can be of therapeutic potential, such as proteins, or miRNAs to inhibit relevant inflammatory pathways 41,42 via both reactive astrocytes and activated microglia 59,60 . Ultimately, EVs likely mitigate ALS pathology through broad impacts on antioxidant and antiapoptotic pathways.…”

“…53,57,58 While more research is needed to determine the exact miRNAs altered in ALS, multiple studies have demonstrated upregulated miR-146a, miR-151a, and miR-3919-3p and downregulated miR-4454 and miR-4286. 56,57,59,60 Briefly, miR-146a regulates low-molecular-weight neurofilament mRNA-another potential ALS biomarker-and is associated with neuroinflammation, miR-151a relates to cellular responses to oxidative stress, miR-4454 downregulation has been linked to dysregulated cell…”

“…EVs are an optimal way to quantify miRNAs, as they reflect the state of the source cell from which the EV was derived, protect miRNAs from degradation via their phospholipid bilayer, and can pass through blood–CNS barriers due to their lipophilic nature 53,57,58 . While more research is needed to determine the exact miRNAs altered in ALS, multiple studies have demonstrated upregulated miR‐146a, miR‐151a, and miR‐3919‐3p and downregulated miR‐4454 and miR‐4286 56,57,59,60 . Briefly, miR‐146a regulates low‐molecular‐weight neurofilament mRNA—another potential ALS biomarker—and is associated with neuroinflammation, miR‐151a relates to cellular responses to oxidative stress, miR‐4454 downregulation has been linked to dysregulated cell proliferation 57,61,62 .…”

Exosomes in brain diseases: Pathogenesis and therapeutic targets

“…Protein dysfunction is present in ALS, and the best treatment is to restore protein homeostasis for proper protein folding. 245 , 246 S2RM stem cells were injected into the nervous system and spread through exosomes to restore protein homeostasis. 167 This suggests that exosome contents can be protected in vivo before reaching the neural targets.…”