An exosome is an extracellular vesicle with a phospholipid bilayer membrane structure and a diameter ranging from 30 to 100 nm. The surface membrane proteins and exosome contents provide a rich source of biomarkers for various pathological conditions and antigens presented to immune cells through participation in cellular signaling. The contents of exosomes are closely associated with their parent cells and include diversified proteins, lipids, noncoding RNA (which include circular RNA and microRNA [miRNA]), and other molecules, which may transport the exosome contents to neighboring or more distant cells. Thus, exosomes represent a novel form of intercellular communication among cells without cell-to-cell direct contact. With the help of exosomes, cells may change their levels of proteins, lipids, and nucleic acids.
Exosomes are secreted from diverse sites and are found in various body fluids such as blood, urine, saliva, breast milk, amniotic fluid, and cerebrospinal fluid. In the central nervous system (CNS), both neurons and neuroglial cells can secrete and release exosomes into the extracellular environment, suggesting a diversified and important functions of exosomes.
Protein aggregation and the formation of inclusion bodies in selected areas of the nervous system due to neuronal cell death is an important cause of neurodegenerative diseases. MiRNAs regulate the level of proteins by regulating levels of mRNAs. Alterations in the expression profile of miRNAs in Alzheimer's disease (AD) patients, Parkinson's disease (PD) patients, amyotrophic lateral sclerosis (ALS) patients, and Huntington's disease (HD) prodromal patients illustrate the important role of miRNAs in neurodegenerative diseases. Dysregulation of miRNAs is closely related with AD, PD, HD, and ALS.
Understanding the network regulation of exosomes and miRNAs in neurodegenerative diseases will aid in the understanding of the pathogenesis of neurodegenerative diseases and identification of valuable biomarkers.
Exosomes' formation involves a series of complex processes. Understanding the generation of exosomes may help better understand their functions [Figure 1]. The generation of exosomes is initiated by early endosomes (EEs) formed from internal budding of the plasma membrane. EEs interact with the Golgi complex to form late endosomes (LEs) or multivesicular bodies (MVBs), which further form intraluminal vesicles (ILVs, i.e., exosomes) through internal budding of the plasma membrane. During this process, molecules including the endosomal sorting complex required for transport, lipids (such as ceramide), and tetraspanins participate in ILV formation. The MVBs formed can either be degraded by fusing with lysosomes or released into the extracellular space as exosomes by fusing with the plasma membrane. RAB proteins including RAB11, RAB27, and RAB35 participate in the trafficking of MVBs to the plasma membrane and in the secretion of exosomes.
BIOGENESIS OF MIRNAS AND SORTING MECHANISM OF EXOSOMAL MIRNAS
Genesis of miRNAs
The formation of mature miRNAs involves several steps [Figure 2]. First, by interacting with RNA polymerase II, the miRNA genes are transcribed to primary miRNA transcript (pri-miRNA), which has long sequences and presents some transcription characteristics of RNA polymerase II such as 5' cap structure and 3' poly (A) tail. Pri-miRNA is cleaved by intranuclear RNase III Drosha to produce precursor miRNA (pre-miRNA), which have a length of 70 nt and feature a stem-loop structure. With no or little enzymatic activity, Drosha needs the help of DGCR8 to catalyze its RNA substrate. The pre-miRNA produced is transported into the cytoplasm by the Ran-GTP-dependent nucleocytoplasmic transporter Exportin 5, which is located in the cell membrane. Exportin 5 can recognize and avidly bind pre-miRNA containing a protruding 3' arm and protects the integrity of this 3' region during the transport of pre-miRNA from the nucleus to the cytoplasm. In the cytoplasm, the pre-miRNA is further cleaved by RNase III Dicer to form mature miRNA with 21-23 nt. The miRNA is then conveyed to the RNA-induced silencing complex (RISC) to form miRNA RISC (miRISC), which recognizes and combines with the 3' untranslated region (3'UTR) of mRNA through a miRNA-specific sequence. miRISC also mediates the degradation of mRNA or inhibits its translation. Ago 1 and Ago 2 have vital roles in the miRISC-mediated silencing.
The mechanism of micro RNAs sorting to exosomes
According to current studies, mature miRNAs are sorted into exosomes through six potential mechanisms [Figure 2].
The first is the miRNA motif and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1)-dependent pathway. The short sequence motifs over-represented in miRNAs (EXOmotifs) guide miRNA sorting into exosomes. Mutation of EXOmotifs will affect miRNA content in the exosomes. HnRNPA2B1 is a RNA-binding protein that can regulate the transport and subcellular localization of mRNA in neurons. HnRNPA2B1 is sumoylated in the cytoplasm and specifically combines with the EXOmotifs (GGAG) to regulate sorting of miRNAs into exosomes.
The second is neutral sphingomyelinase 2 (nSMase2)-dependent pathway. Blocking or overexpressing the activity of nSMase2 reduces and increases the quantity of miRNAs sorted into exosomes, respectively.
The third is the 3' end of the miRNA sequence-dependent pathway. Koppers-Lalic et al. studied the exosomes secreted by maternal B cells and found that the 3' end-rich poly (A) of a miRNA is more abundant in B cells, while the 3' end-rich poly (U) of a miRNA is more abundant in the exosomes originating from B cells. This indicates a potential exosome sorting pathway for miRNA.
The fourth is the endogenous RNA-mediated pathway. Squadrito et al. described that the altered expression of miRNA target mRNA in macrophages can regulate miRNA sorting into exosomes by facilitating the transport of miRNA from the cytoplasm to MVBs.
The fifth is the Ago2-dependent pathway. Ago2 is a component of the RISC. McKenize et al. found that the overactive KRAS genes of KRAS-mutant cells inhibit the localization of Ago2 in the multivesicular endosomes and reduce the secretion of Ago2 into the exosomes, where the level of Ago2 regulates the sorting of miRNA into exosomes.
The sixth is the Y-box binding protein 1 (YBX1)-dependent pathway. YBX1 is a RNA-binding protein. Shurtleff et al. reported that YBX1 can bind mi-233 and help it sort into exosomes. However, the authors did not find evidence of any role of Ago2 in the sorting of mi-233 into exosomes.
CRITICAL ROLES OF EXOSOMES AND MIRNAS IN NEURODEGENERATIVE DISEASES
Exosomes: mediators of neurodegeneration, neuroprotection, and therapeutics
Neuroglial cells include different subsets, which jointly maintain nerve homeostasis, signal transduction, and cellular communication, implying a close cooperation between neurons and neuroglial cells. In the CNS, neurons, microglia, astrocytes, and oligodendrocytes can secrete microvesicles into the extracellular environment. These microvesicles or exosomes play a vital role in the occurrence and progression of neurodegenerative diseases, in addition to regulating normal brain functions such as the development and repair of neurons and maintenance of synaptic function [Figure 3].
The main pathological characteristics of AD are excessive accumulation of extracellular senile plaques (composed of amyloid-β peptide [Aβ]) and intracellular neurofibrillary tangles (NFTs) containing hyperphosphorylated tau protein, which can degenerate neurons and activate microglia and astrocytes to produce pro-inflammatory cytokines. The inflammatory environment triggers alteration in the nervous system and breaches the blood–brain barrier (BBB), thus inducing AD. β cleavage of amyloid precursor protein (APP) occurs in EEs to produce Aβ, which enters MVBs and is secreted into the extracellular space in the form of exosomes. Aβ can be transported by the exosomes to lysosome where it is degraded. Disorder of this clearance pathway will cause accumulation of Aβ, leading to the occurrence of AD.
PD is the second most common neurodegenerative disorder after AD. PD is characterized by degeneration and death of dopaminergic (DA) neurons in the substantia nigra pars compacta and formation of intracytoplasmic eosinophilic inclusion bodies (termed Lewy bodies) in the surviving neurons, where α-synuclein (α-syn), as the primary component, abnormally accumulates. Although most cases of PD are sporadic, familial cases have also been associated with different genes that include SNCA, leucine-rich receptor kinase 2 (LRRK2), PARKIN, PTEN-induced kinase 1, and DJ-1. As a pathogenic factor, α-syn has a vital association with exosomes. Emmanouilidou et al. found that α-syn monomers and polymers produced by neuroblastoma cells are secreted to the extracellular space through exosomes using a calcium-dependent mechanism and cause the death of neuron recipient cells. Alvarez et al. subsequently reported a similar phenomenon where cultured SY5Y neuroblastoma cells released α-syn through exosomes secreted to the extracellular space. Exosomes play a critical role in PD. They transport α-syn to lysosomes for degradation. Disorder of this clearance pathway results in the escape and degradation of α-syn and the exosome-mediated transport of the components to recipient cells. LRRK2 plays a vital role in the secretion of exosomes and fusing of MVBs with the membrane. LRRK2 R1441C mutation induces the formation of aberrant MVBs and disrupts the balance between the formation and clearance of MVBs, consequently leading to PD. In addition, the autophagic system will also help α-syn escape degradation. Accumulated α-syn will form MVBs, followed by exosome secretion to the extracellular space. Adjoining cells take up exosomes by phagocytosis, followed by the intracellular release and accumulation of α-syn, resulting in cytotoxicity. Exosomes can serve as a biomarker for the diagnosis of PD.
HD is an autosomal dominant-inherited neurodegenerative disease caused by mutation of Huntingtin (HTT). Mutated HTT (mHTT) will cause alterations in protein conformation, resulting in aberrant aggregation in cells, neuronal death, and progressive neurodegeneration. Huntington-associated protein 1 (HAP1) and mHTT have high affinity and can interact with hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), which can recognize and recruit ubiquitinated substrate and aid its entry into the MVBs-mediated sorting and degradation pathway. Overexpressed HAP1 can effectively block the transport of epidermal growth factor receptor (EGFR) from EEs to LEs, inhibit the degradation of internalized EGFR, enhance the activity of the signal pathway of EGFR, and reduce the cytotoxicity caused by mHTT. Recent studies described that exosomes from adipose-derived stem cells (ASC-exo) can significantly reduce the accumulation of mHTT in R6/2 mouse-derived neurons, indicating a potential effect of ASC-exo in the therapy of HD.
Cytoplasmic TAR DNA-binding protein 43 (TDP-43) aggregation is an important pathological hallmark of ALS and frontotemporal lobar degeneration. The TDP-43 protein is present in blood and cerebrospinal fluid. Nonaka et al. introduced insoluble TDP-43 protein from ALS patients into SH-SY5Y cells and reported aggregation of the protein in a self-template manner. The findings demonstrated that the accumulation of pathological TDP-43 protein has prion-like properties. Related studies demonstrated that protein aggregation and autophagy inhibition promote the secretion of exosome TDP-43 from Neuro2a cells and primary neurons. Exposure of Neuro2a cells to exosomes from patients with ALS causes TDP-43 to accumulate in Neuro2a cells, suggesting that exosomes are involved in the propagation of TDP-43. However, inhibition of exosome secretion by inactivation of nSMase2 with GW4869 or by silencing with RAB27A also produced accumulation of TDP-43 in Neuro2a cells, suggesting that exosomes containing pathological TDP-43 play an important role not only in the transmission of TDP-43 but also in the transport and clearance of pathological TDP-43.
Neurodegenerative diseases involve a common molecular and cellular mechanism of misfolding and accumulation of proteins and formation of inclusion bodies in specific brain regions. Under normal conditions, exosomes can transport the accumulated proteins to lysosomes or extracellular plasma for degradation. Under pathological conditions, clearance is disrupted. Knowledge of the pathogenesis of this clearance pathway is necessary to understand the potential therapy of neurodegenerative diseases.
Effect of regulatory dysregulation of micro RNAs on neurodegenerative diseases
MiRNAs are a type of small regulatory RNA molecules with a length of 21–23 nt; those participate in various physiological processes associated with neurodegenerative diseases such as AD, PD, and HD. MiRNAs contribute to neurodegenerative diseases primarily by three pathways: (1) inhibition of the translation of proteins or degrading proteins through target regulation-related gene mRNA; (2) participation in neuroinflammation by directly combining with toll-like receptor (TLR) or regulating TLR mRNA expression; and (3) miRNA formation disorder [Figure 3].
Micro RNA-targeting genes in neurodegenerative diseases
Aβ and hyperphosphorylated tau protein are the key factors that cause AD. They are individually regulated by APP, presenilin-1 (PS1), PS2, and tau protein genes. The genes can be regulated by miRNA [Table 1].
Increase in Aβ level caused by increased APP will lead to synaptic function disorder and degeneration of neurons and eventually will cause cognitive decline. Recent studies have found that the miR-200b, miR-429, and miR-20a family (including miR-20a, miR-106b, and miR-17-5p), miR-16, and miR-101 can downregulate the expression of APP. The expression of proteins translated from the PS1 gene and PS2 gene is the components of γ-secretase. Mutations in these proteins cause increased γ-secretase activity, which is closely related with the generation of Aβ. A study of the expression profile of miRNA in PS1-knockout mouse brain tissue found that downregulation of miR-9 expression was related with neurodegenerative diseases. Other studies further found that miR-9 also participates in regulating the neurogenesis of zebrafish and mice. The tau protein, which is abundant in neurons, is a kind of microtubule-associated protein (MAP). Tau protein molecule with normal biological function contains two to three phosphate groups. However, in AD patients, tau protein is abnormally hyperphosphorylated and contains five to nine phosphate groups, and is dissociated from microtubules and aggregates in neuron soma and dendrites to form NFTs. In M17D cells, miR-34a directly combines with the 3'-UTR of MAP-tau to inhibit the expression of endogenous tau protein. In addition, miR-125b activates kinases, such as ERK1/2 and CDK5/P35, by inhibiting the expression of DUSP6 and PPP1CA, thus leading to hyperphosphorylation of tau protein. Related clinical studies have found that the blood of mild cognitive impairment (MCI) and dementia of Alzheimer-type (DAT) patients contains lower levels of exosomal miR-193b compared with that in controls, with lower content in DAT patients compared to that in patients with MCI. In addition, the exosomal miR-193b in the cerebrospinal fluid of DAT patients is lower than that of the controls, indicating that miR-193b can be used as a biomarker for the diagnosis of AD.
The aberrant expression and accumulation of α-syn are crucial in the pathogenesis of PD. Overexpressed α-syn can be toxic to dopamine neurons. Shamsuzzama et al. developed and studied the transgenic Caenorhabditis elegans (C. elegans) and miRNA let-7 functionally deleted transgenic C. elegans models and found that let-7 functional deletion decreased α-syn expression but did not influence dopamine neurons. In sporadic PD cases, several genome-wide association studies had reported that the α-syn gene (SNCA) is one of the genomic loci posing the highest risk in patients. McMillan et al. found that miR-7 can combine with the 3'-UTR of SNCA mRNA to inhibit its transcription and regulate the expression of α-syn. The authors further found that the expression of miR-7 was decreased in the substantia nigra of the brain of PD patients, suggesting a potential action of miR-7 in the therapy of PD. Moreover, Chen et al. found significantly upregulated expression of hsa-miR-4639-5p in the blood plasma of PD patients and reported the downregulation of the DJ-1 protein level by negatively regulating the posttranscription level of the PD-associated gene DJ-1, eventually causing severe oxidative stress and neuronal death. The authors considered that hsa-miR-4639-5p can serve as a biomarker for early PD diagnosis. In addition, Hoss et al. studied the miRNA expression profiles in the prefrontal cortex of controls and PD patients screened for miR-10b-5p. The significant decrease of miR-10b-5p expression in PD patients suggested that miR-10b-5p could be used as a molecular marker for the clinical diagnosis of PD [Table 1].
HD is an autosomal dominant-inherited neurodegenerative disease that results from the encoded HTT polyglutamine sequence lengthened by the CAG trinucleotide repeat mutations in exon 1 of the IT15 gene. The mHTT gene exon 1 (mHTT-Exon-1) can directly bind genomic DNA and alter its conformation, leading to altered gene expression. When mHTT-Exon-1 is overexpressed in NT2 cells, the miR-34b expression level will significantly increase. Inhibiting the miR-34b expression will reduce the distribution of mHTT in cytoplasm and its in vitro toxicity. However, miR-27a can increase the expression level of multidrug resistance protein-1 (MDR-1) when used to transfect R6/2 HD mouse-derived NSC cells. MDR-1 can transport mHTT and eventually reduce the accumulation of mHTT in cells [Table 1].
Activation of toll-like receptors by micro RNAs in neuroinflammation
Many neurodegenerative diseases are related with inflammation, which can increase cell injury and cause neuronal death. TLR is a type of innate immune receptor that when activated can activate the downstream signal molecules through the MyD88-dependent or independent pathway, eventually causing the release of inflammatory factors. TLRs of microglia and neurons can also cause CNS injury even in the absence of an obvious pathogen, indicating that the ligand of activated TLRs probably originates from the host. In unaffected or undamaged cells, miRNA can activate TLRs as a physiological ligand and also as damage-associated molecular patterns to trigger an immune response. TLR7 is localized in endosomes, where it can recognize RNA viruses and is expressed in the neuronal cells. Lehmann et al. found that miRNA let-7 can activate TLR7 in neuronal cells and consequently causes neurodegenerative diseases, while TLR7-deleted mice can resist the influence of neurodegenerative diseases [Figure 3]. Later, data have more convincingly demonstrated that neurons can activate the TLR7 located in endosomes and further activate MyD88 and the downstream signal molecules through the uptake of the exosomes containing let-7, eventually causing death of neurons. In general, TLRs display a wide range of expressions in the CNS. Examples include the expressions of TLR3, 4, 7, and 9 in human neuronal cells, expressions of TLR2 in human oligodendrocytes, expression of TLR3-4 in human astrocytes, and expression of TLR1-4 in human microglia. We can speculate that miRNAs play a critical role in activating TLRs to cause inflammation and consequently cause neurodegenerative diseases. Supporting data are needed.
MiRNA-generating disorders in neurodegenerative diseases
Drosha and Dicer are the two types of RNase III enzymes. They are critical to the formation of miRNAs. They individually catalyze the sequence cleaving in the process of miRNAs maturation. The deficiency or formation disorder of these two enzymes is closely related to neurodegenerative diseases. TDP-43 protein is vital for the maturation of miRNAs. In ALS patients, mutated TDP-43 will combine with heterogeneous nuclear ribonucleoproteins family proteins and Drosha to form a complex. Similarly, the deficiency of Dicer can impair the expression of minor miRNAs in adult forebrain and eventually cause hyperphosphorylation of tau proteins, consequently leading to neuron death. The deficiency of Dicer will also cause the accumulation of Aβ and loss of dopamine [Figure 3]. For example, miR-133b, which is highly expressed in the midbrain under normal conditions, is deficiently expressed in PD patients and in an animal model of PD owing to deficiency of Dicer.
The collective results that have been presented show that miRNAs play a vital regulation role in the CDN under normal and pathological conditions. Moreover, the occurrence of neurodegenerative diseases caused by miRNA-activated TLRs implies that miRNA may have many other regulatory functions, which require further research.
Exosomes act as a conduit for cell-to-cell communication. Their components can reflect the function status of the cells of origin, contain cytopathic molecular information, and aid in the diagnosis of diseases. Owing to their cargo function, nanometer size, and ability to cross the BBB, advantages in therapeutic effect, targeting ability, immune response, and safety, exosomes provide a novel approach for treatment of neurodegenerative diseases and brain-targeted drug delivery. This review highlights a wide range of regulatory functions of miRNAs in the CNS. Exosomes can transport let-7 to activate TLR7. This implies a novel regulation mechanism for neuroinflammation. Furthermore, abnormal expression of miRNA has been confirmed in a patient with neurodegenerative disease. miRNAs are a type of small RNA molecule those extensively regulate physiological and pathological processes. They can be used as biomarkers for early diagnosis of neurodegenerative diseases. In CNS regulatory processes, exosomes and miRNAs form a network to regulate CNS homeostasis, both synergistically and individually.
Great progress has been made in the studies on neurodegenerative diseases such as AD, PD, HD, and ALS. However, there are still many problems to be solved and therapies for these diseases are mostly conservative at present. These diseases remain incurable. Taking AD as an example, there is no drug to delay or prevent the progression of AD. Exosomes and miRNAs offer the potential for the diagnosis and treatment of neurodegenerative diseases.
Financial support and sponsorship
This study was supported by a grant of Institute of Environmental Science of China West Normal University, Environmental Education Center of China West Normal University and Research Projects for Young Teachers of China West Normal University (No. 416535).
Conflicts of interest
There are no conflicts of interest.
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Edited by: Yuan-Yuan Ji