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Review
. 2022 Jul;19(4):1119-1132.
doi: 10.1007/s13311-022-01232-9. Epub 2022 Apr 14.

Pathogenic Extracellular Vesicle (EV) Signaling in Amyotrophic Lateral Sclerosis (ALS)

Gloria Kim  1 , Xuan Chen  1 , Yongjie Yang  2   3
Affiliations
Review

Pathogenic Extracellular Vesicle (EV) Signaling in Amyotrophic Lateral Sclerosis (ALS)

Gloria Kim et al. Neurotherapeutics. 2022 Jul.

Abstract

Extracellular vesicles (EVs), once considered a pathway for cells to remove waste, have now emerged as an important mechanism for intercellular communication. EVs are particularly appealing in understanding the central nervous system (CNS) communication, given that there are very diverse cell types in the CNS and constant communications among various cells to respond to the frequently changing environment. While they are heterogeneous and new vesicles are continuously to be discovered, EVs are primarily classified as plasma membrane-derived microvesicles (MVs) and endosome-derived exosomes. Secretion of EVs has been shown from all CNS cell types in vitro and intercellular EV signaling has been implicated in neural development, axon integrity, neuron to glia communication, and propagation of protein aggregates formed by disease pathogenic proteins. However, significant hurdles remain to be tackled in understanding their physiological and pathological roles as well as how they can be developed as biomarkers or new therapeutics. Here we provide our summary on the known cell biology of EVs and discuss opportunities and challenges in understanding EV biology in the CNS and particularly their involvement in ALS pathogenesis.

Keywords: ALS; ESCRT; EV; Exosome; Neuron to glia communication; Tetraspanin.

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Figures

Fig. 1
Fig. 1
Common lab approaches for EV isolation. A. Ultracentrifugation (including density gradient centrifugation); B. Polymeric precipitation; PEG: Polyethylene glycol; C. Size exclusion chromatography (SEC); D. Immunoaffinity-based purification of EVs. Major pros and cons for each approach are described
Fig. 2
Fig. 2
Currently reported EV-mediated intercellular communication in CNS cell-types. Representative specific signals identified in CNS cell-derived EVs/exosomes were shown. miRs: microRNA; The size of the arrows indicates relative number of studies reported so far about the indicated intercellular communications. N: neurons; A: astroglia; O: Oligodendrocytes; M: microglia
Fig. 3
Fig. 3
Potential involvement of CNS cell-type specific EVs in the propagation of various protein aggregates in neurodegenerative diseases. Stressed neuron-derived aggregate-containing EVs can either be taken up directly into healthy neurons or be phagocytosed into microglia or astroglia and then secreted in EVs to be taken up by healthy neurons. Representative disease-relevant mutant protein aggregates were shown. EVs secreted from neurons, microglia, or astroglia are in grey, blue, and purple, respectively. EVs in red indicate protein aggregate-containing EVs from different cell types
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