ReviewEmerging roles of extracellular vesicles in neurodegenerative disorders
Introduction
Extracellular vesicles (EVs) are small membranous vesicles bounded by a lipid bilayer and carrying diverse intraluminal cargos of proteins, lipids, and nucleic acids which are secreted into the extracellular milieu (Thompson et al., 2016). The secretion of EVs was initially described as a consequence of eliminating unneeded compounds from the cell (Johnstone et al., 1987). However, EVs are now known to play vital roles in the intercellular communication that underlies various physiological processes and pathological functions of both recipient and parent cells (Yanez-Mo et al., 2015). The creation of EVs is conserved throughout evolution from bacteria to humans (Schorey et al., 2015). To our knowledge, EVs are most commonly grouped into three broad types according to their biogenesis: exosomes, microvesicles (MVs) and apoptotic bodies (Table 1) (Yanez-Mo et al., 2015). Most studies have focused on exosomes and microvesicles (Kalra et al., 2012). They are released from almost all cell types, including the cells of central nervous system (CNS) (Ciregia et al., 2017), and their functions in CNS are currently under active investigation (Asai et al., 2015; Chiarini et al., 2017; Kramer-Albers et al., 2007). Here, we examine the knowledge of EVs biology, focus on their roles in neurodegenerative disorders, and discuss their involvement in pathogenesis as well as in biomarkers for these diseases.
Section snippets
Exosomes
Exosomes, which were first termed in the 1980s (Johnstone et al., 1987), are small extracellular nano-size vesicles with typically 30–150 nm in diameter (DeLeo and Ikezu, 2018). Early endosomes undergo inward budding to form multivesicular bodies (MVBs) that contain intraluminal vesicles (ILVs) (Colombo et al., 2014). By fusion of MVBs with the plasma membrane, ILVs are released into the extracellular environment as exosomes (Heijnen et al., 1999). Alternatively, MVBs can be fused with the
EV Cargos: nucleic acids and proteins
EVs were initially regarded as “body dust” and a consequence of loading unneeded compounds from the cell (Johnstone et al., 1987; Wolf, 1967). A major breakthrough was the observation of nucleic acids (both mRNA and miRNA) in EVs and their transfer between cells mediated through EVs (Ratajczak et al., 2006; Valadi et al., 2007). Recently, various species of RNA have been detected within EVs. In addition to mRNA and miRNA, a large number of noncoding RNA, circular RNA, ribosomal RNA, transfer
Biogenesis of EVs
Because exosomes and microvesicles differ from their derivation, the cellular machineries involved in their formation and release are likely different in spite of the overlapped mechanistic components (Fig. 1). The ESCRT-dependent mechanism was initially interpreted as the biogenesis of ILVs and MVBs, thereafter giving rise to the speculation on its potential role in exosome formation (Hurley, 2008; Juan and Furthauer, 2018). It’s known that the ESCRT machinery mediates the formation of ILVs in
Uptake of EVs by recipient cells
After entering into the extracellular space, EVs can target to recipient cells and deliver their cargos which mediate the physiological processes and pathological progress. EV uptake requires the interactions with surface receptors at the plasma membrane, followed by their fusion with target cells or endocytosis (Mulcahy et al., 2014). Several molecules including integrins, tetraspanins, lipids, lectins, proteoglycans, and extracellular matrix (ECM) components, are known to mediate these
EVs in the CNS and neurodegenerative disorders
Both neurons and glia in the nervous system are known to release EVs (Budnik et al., 2016; Perez-Gonzalez et al., 2012). These EVs can move from the central nervous system to the systemic circulation by direct transfer into capillaries or through interstitial fluid into the CSF (Thompson et al., 2016; Zakharov et al., 2003). In several experiments, EVs isolated from body fluids such as blood and cerebrospinal fluid (CSF) are shown to contain neuron- or glia-specific markers. For example, Goetzl
Discussion
In the past decade, the major progress on EVs was finding their active roles in cell-to-cell communication, both under healthy and pathological conditions. The properties that EVs can be accessibly isolated from biofluids and carry cell-specific cargoes, including proteins and nucleotides, give them the potential to harbor disease-specific molecular signatures (Thompson et al., 2016). Therefore, vesicles have been proposed as useful candidate biomarkers as well as promising therapeutic targets
Acknowledgements
We would like to thank Samuel Hersh for editing the manuscript. This work is funded in part by Nancy Lurie Marks Family Foundation (TI), Robert E. Landreth and Dona Landreth Family Foundation (TI), BrightFocus Foundation (A2016551S), Cure Alzheimer’s Fund, NIH R01AG054672 (TI), RF1AG054199 (TI), R56AG057469(TI), R21NS104609 (TI).
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