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Exosomes are lipid-bilayered vesicles, originating from early endosomes that capture cellular proteins and genetic materials to form multi-vesicular bodies. These exosomes are secreted into extracellular fluids such as cerebrospinal fluid, blood, urine, and cell culture supernatants. They play a key role in intercellular communication by carrying active molecules like lipids, cytokines, growth factors, metabolites, proteins, and RNAs. Recently, the potential of exosomal delivery for therapeutic purposes has been explored due to their low immunogenicity, nano-scale size, and ability to cross cellular barriers. This review comprehensively examines the biogenesis of exosomes, their isolation techniques, and their diverse applications in theranostics. We delve into the mechanisms and methods for loading exosomes with mRNA, miRNA, proteins, and drugs, highlighting their transformative role in delivering therapeutic payloads. Additionally, the utility of exosomes in stem cell therapy is discussed, showcasing their potential in regenerative medicine. Insights into exosome cargo using pre- or post-loading techniques are critical for exosome theranostics. We review exosome databases such as ExoCarta, Expedia, and ExoBCD, which document exosome cargo. From these databases, we identified 25 proteins common to both exosomes and P-bodies, known for mutations in the COSMIC database. Exosome databases do not integrate with mutation analysis programs; hence, we performed mutation analysis using additional databases. Accounting for the mutation status of parental cells and exosomal cargo is crucial in exosome theranostics. This review provides a comprehensive report on exosome databases, proteins common to exosomes and P-bodies, and their mutation analysis, along with the latest studies on exosome-engineered theranostics.
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Exossomos , Mutação , Exossomos/metabolismo , Exossomos/genética , Humanos , AnimaisRESUMO
Ferroptosis, which comprises iron-dependent cell death, is crucial in cancer and non-cancer treatments. Exosomes, the extracellular vesicles, may deliver biomolecules to regulate disease progression. The interplay between ferroptosis and exosomes may modulate cancer development but is rarely investigated in natural product treatments and their modulating miRNAs. This review focuses on the ferroptosis-modulating effects of natural products and miRNAs concerning their participation in ferroptosis and exosome biogenesis (secretion and assembly)-related targets in cancer and non-cancer cells. Natural products and miRNAs with ferroptosis-modulating effects were retrieved and organized. Next, a literature search established the connection of a panel of ferroptosis-modulating genes to these ferroptosis-associated natural products. Moreover, ferroptosis-associated miRNAs were inputted into the miRNA database (miRDB) to bioinformatically search the potential targets for the modulation of ferroptosis and exosome biogenesis. Finally, the literature search provided a connection between ferroptosis-modulating miRNAs and natural products. Consequently, the connections from ferroptosis-miRNA-exosome biogenesis to natural product-based anticancer treatments are well-organized. This review sheds light on the research directions for integrating miRNAs and exosome biogenesis into the ferroptosis-modulating therapeutic effects of natural products on cancer and non-cancer diseases.
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Produtos Biológicos , Exossomos , Ferroptose , MicroRNAs , Neoplasias , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Humanos , Exossomos/metabolismo , Exossomos/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , AnimaisRESUMO
Bone is a metabolically dynamic structure that is generally remodeled throughout the lifetime of an individual but often causes problems with increasing age. A key player for bone development and homeostasis, but also under pathological conditions, is the bone vasculature. This complex system of arteries, veins, and capillaries forms distinct structures where each subset of endothelial cells has important functions. Starting with the basic process of angiogenesis and bone-specific blood vessel formation, coupled with initial bone formation, the importance of different vascular structures is highlighted with respect to how these structures are maintained or changed during homeostasis, aging, and pathological conditions. After exemplifying the current knowledge on bone vasculature, this review will move on to exosomes, a novel hotspot of scientific research. Exosomes will be introduced starting from their discovery via current isolation procedures and state-of-the-art characterization to their role in bone vascular development, homeostasis, and bone regeneration and repair while summarizing the underlying signal transduction pathways. With respect to their role in these processes, especially mesenchymal stem cell-derived extracellular vesicles are of interest, which leads to a discussion on patented applications and an update on ongoing clinical trials. Taken together, this review provides an overview of bone vasculature and bone regeneration, with a major focus on how exosomes influence this intricate system, as they might be useful for therapeutic purposes in the near future.
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Regeneração Óssea , Exossomos , Neovascularização Fisiológica , Humanos , Exossomos/metabolismo , Animais , Osso e Ossos/metabolismo , Osso e Ossos/irrigação sanguínea , Células-Tronco Mesenquimais/metabolismo , Osteogênese , Transdução de Sinais , Células Endoteliais/metabolismo , AngiogêneseRESUMO
Exosomes are among the most puzzling vehicles of intercellular communication, but several crucial aspects of their biogenesis remain elusive, primarily due to the difficulty in purifying vesicles with similar sizes and densities. Here we report an effective methodology for labelling small extracellular vesicles (sEV) using Bodipy FL C16, a fluorescent palmitic acid analogue. In this study, we present compelling evidence that the fluorescent sEV population derived from Bodipy C16-labelled cells represents a discrete subpopulation of small exosomes following an intracellular pathway. Rapid cellular uptake and metabolism of Bodipy C16 resulted in the incorporation of fluorescent phospholipids into intracellular organelles specifically excluding the plasma membrane and ultimately becoming part of the exosomal membrane. Importantly, our fluorescence labelling method facilitated accurate quantification and characterization of exosomes, overcoming the limitations of nonspecific dye incorporation into heterogeneous vesicle populations. The characterization of Bodipy-labelled exosomes reveals their enrichment in tetraspanin markers, particularly CD63 and CD81, and in minor proportion CD9. Moreover, we employed nanoFACS sorting and electron microscopy to confirm the exosomal nature of Bodipy-labelled vesicles. This innovative metabolic labelling approach, based on the fate of a fatty acid, offers new avenues for investigating exosome biogenesis and functional properties in various physiological and pathological contexts.
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Exossomos , Vesículas Extracelulares , Vesículas Extracelulares/metabolismo , Ácido Palmítico/metabolismo , Exossomos/metabolismo , Transporte BiológicoRESUMO
Exosomes are small extracellular vesicles (sEVs) of ~30-150 nm in diameter that have the same topology as the cell, are enriched in selected exosome cargo proteins, and play important roles in health and disease. To address large unanswered questions regarding exosome biology in vivo, we created the exomap1 transgenic mouse model. In response to Cre recombinase, exomap1 mice express HsCD81mNG, a fusion protein between human CD81, the most highly enriched exosome protein yet described, and the bright green fluorescent protein mNeonGreen. As expected, cell type-specific expression of Cre induced the cell type-specific expression of HsCD81mNG in diverse cell types, correctly localized HsCD81mNG to the plasma membrane, and selectively loaded HsCD81mNG into secreted vesicles that have the size (~80 nm), topology (outside out), and content (presence of mouse exosome markers) of exosomes. Furthermore, mouse cells expressing HsCD81mNG released HsCD81mNG-marked exosomes into blood and other biofluids. Using high-resolution, single-exosome analysis by quantitative single molecule localization microscopy, we show here that that hepatocytes contribute ~15% of the blood exosome population whereas neurons contribute <1% of blood exosomes. These estimates of cell type-specific contributions to blood EV population are consistent with the porosity of liver sinusoidal endothelial cells to particles of ~50-300 nm in diameter, as well as with the impermeability of blood-brain and blood-neuron barriers to particles >5 nm in size. Taken together, these results establish the exomap1 mouse as a useful tool for in vivo studies of exosome biology, and for mapping cell type-specific contributions to biofluid exosome populations. In addition, our data confirm that CD81 is a highly-specific marker for exosomes and is not enriched in the larger microvesicle class of EVs.
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Exosomes are 50-200 nm-sized extracellular vesicles that are secreted by cells to transfer signals and communicate with other cells. Recent research has revealed that allograft-specific exosomes containing proteins, lipids, and genetic materials are released into circulation post-transplantation which are powerful indicators of graft failure in solid-organ and tissue transplantations. The macromolecular content of exosomes released by the allograft and the immune cells serve as potential biomarkers for assessing the function and the acceptance/rejection status of the transplanted grafts. Identifying these biomarkers could aid in the development of therapeutic strategies to improve graft longevity. Exosomes can be used to deliver therapeutic agonists/antagonists to grafts and prevent rejection. Inducing long-term graft tolerance has been demonstrated in many studies using exosomes from immunomodulatory cells such as immature DCs, T regulatory cells, and MSCs. The use of graft-specific exosomes for targeted drug therapy has the potential to reduce the unwanted side effects of immunosuppressive drugs. Overall, in this review, we have explored the critical role of exosomes in the recognition and cross-presentation of donor organ-specific antigens during allograft rejection. Additionally, we have discussed the potential of exosomes as a biomarker for monitoring graft function and damage, as well as their potential therapeutic applications in mitigating allograft rejection.
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Exossomos , Exossomos/metabolismo , Rejeição de Enxerto/prevenção & controle , Transplante Homólogo , Aloenxertos , Biomarcadores/metabolismoRESUMO
Exosomes transport a variety of macromolecules and modulate intercellular communication in physiology and disease. However, the regulation mechanisms that determine exosome contents during exosome biogenesis remain poorly understood. Here, we find that GPR143, an atypical GPCR, controls the endosomal sorting complex required for the transport (ESCRT)-dependent exosome biogenesis pathway. GPR143 interacts with HRS (an ESCRT-0 Subunit) and promotes its association to cargo proteins, such as EGFR, which subsequently enables selective protein sorting into intraluminal vesicles (ILVs) in multivesicular bodies (MVBs). GPR143 is elevated in multiple cancers, and quantitative proteomic and RNA profiling of exosomes in human cancer cell lines showed that the GPR143-ESCRT pathway promotes secretion of exosomes that carry unique cargo, including integrins signaling proteins. Through gain- and loss-of-function studies in mice, we show that GPR143 promotes metastasis by secreting exosomes and increasing cancer cell motility/invasion through the integrin/FAK/Src pathway. These findings provide a mechanism for regulating the exosomal proteome and demonstrate its ability to promote cancer cell motility.
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Exossomos , Neoplasias , Humanos , Animais , Camundongos , Exossomos/metabolismo , Proteômica , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Transporte Proteico , Transporte Biológico , Corpos Multivesiculares/metabolismo , Neoplasias/metabolismo , Proteínas do Olho/metabolismo , Glicoproteínas de Membrana/metabolismoRESUMO
Exosomes are a subtype of membrane-contained vesicles 40-200 nm in diameter that are secreted by cells into their surroundings. By transporting proteins, lipids, mRNA, miRNA, lncRNA, and DNA, exosomes are able to perform such vital functions as maintaining cellular homeostasis, removing cellular debris, and facilitating intercellular and interorgan communication. Exosomes travel in all body fluids and deliver their molecular messages in autocrine, paracrine as well as endocrine manners. In recent years, there has been an increased interest in studying exosomes as diagnostic markers and therapeutic targets, since in many disease conditions this machinery becomes dysregulated or hijacked by pathological processes. Additionally, delivery of exosomes and exosomal miRNA has already been shown to improve systemic metabolism and inhibit progression of cancer development in mice. However, the subcellular machinery of exosomes, including their biogenesis, release and uptake, remains largely unknown. This review will bring molecular details of these processes up to date with the goal of expanding the knowledge basis for designing impactful exosome experiments in the future.
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Exossomos , MicroRNAs , Animais , Camundongos , Exossomos/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Transporte BiológicoRESUMO
It has been shown that type 2 Diabetes Mellitus (T2DM) changes the paracrine activity of several cell types. Whether the biogenesis of exosomes is changed during diabetic conditions is the subject of debate. Here, we investigated the effect of T2M on exosome biogenesis in rat pulmonary tissue. Rats received a high-fat diet regime and a single low dose of Streptozocin to mimic the T2DM-like condition. A total of 8 weeks after induction of T2DM, rats were subjected to several analyses. Besides histological examination, vascular cell adhesion molecule 1 (VCAM-1) levels were detected using immunohistochemistry (IHC) staining. Transcription of several genes such as IL-1ß, Alix, and Rab27b was calculated by real-time polymerase chain reaction assay. Using western blot analysis, intracellular CD63 levels were measured. The morphology and exosome secretion activity were assessed using acetylcholinesterase (AChE) assay and scanning electron microscopy, respectively. Histological results exhibited a moderate-to-high rate of interstitial pneumonia with emphysematous changes. IHC staining showed an increased VCAM-1 expression in the diabetic lungs compared with the normal conditions (p < .05). Likewise, we found the induction of IL-1ß, and exosome-related genes Alix and Rab27b under diabetic conditions compared with the control group (p < .05). Along with these changes, protein levels of CD63 and AChE activity were induced upon the initiation of T2DM, indicating accelerated exosome biogenesis. Taken together, current data indicated the induction of exosome biogenesis in rat pulmonary tissue affected by T2DM. It seems that the induction of inflammatory niche is touted as a stimulatory factor to accelerate exosome secretion.
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Diabetes Mellitus Tipo 2 , Exossomos , Pneumonia , Ratos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Exossomos/metabolismo , Acetilcolinesterase/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Inflamação/metabolismo , Pneumonia/metabolismo , Pulmão/metabolismoRESUMO
Exosomes are small extracellular vesicles (sEVs) of ~30-150 nm in diameter that are enriched in exosome marker proteins and play important roles in health and disease. To address large unanswered questions regarding exosome biology in vivo, we created the Exomap1 transgenic mouse, which in response to Cre recombinase expresses the most highly enriched exosomal marker protein known, human CD81, fused to mNeonGreen (HsCD81mNG), and prior to Cre expresses a mitochondrial red fluorescent protein. Validation of the exomap1 mouse with eight distinct Cre drivers demonstrated that HsCD81mNG was expressed only in response to Cre, that murine cells correctly localized HsCD81mNG to the plasma membrane, and that this led to the secretion of HsCD81mNG in EVs that had the size (~70-80 nm), topology, and composition of exosomes. Furthermore, cell type-specific activation of the exomap1 transgene allowed us to use quantitative single molecule localization microscopy to calculate the cell type-specific contribution to biofluid exosome populations. Specifically, we show that neurons contribute ~1% to plasma and cerebrospinal fluid exosome populations whereas hepatocytes contribute ~15% to plasma exosome populations, numbers that reflect the known vascular permeabilities of brain and liver. These observations validate the use of Exomap1 mouse models for in vivo studies of exosome biology.
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Exosomes, a type of extracellular vesicle with a diameter of approximately 100 nm that is secreted by all cells, regulate the phenotype and function of recipient cells by carrying molecules such as proteins, nucleic acids, and lipids and are important mediators of intercellular communication. Exosomes are involved in various physiological and pathological processes such as immunomodulation, angiogenesis, tumorigenesis, metastasis, and chemoresistance. Due to their excellent properties, exosomes have shown their potential application in the clinical diagnosis and treatment of disease. The functions of exosomes depend on their biogenesis, uptake, and composition. Thus, a deeper understanding of these processes and regulatory mechanisms can help to find new targets for disease diagnosis and therapy. Therefore, this review summarizes and integrates the recent advances in the regulatory mechanisms of the entire biological process of exosomes, starting from the formation of early-sorting endosomes (ESCs) by plasma membrane invagination to the release of exosomes by fusion of multivesicular bodies (MVBs) with the plasma membrane, as well as the regulatory process of the interactions between exosomes and recipient cells. We also describe and discuss the regulatory mechanisms of exosome production in tumor cells and the potential of exosomes used in cancer diagnosis and therapy.
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Exossomos , Vesículas Extracelulares , Endossomos , Vesículas Transportadoras , Transporte BiológicoRESUMO
This study was conducted to investigate the inhibitory effects of light-emitting diodes (LEDs) on exosome biogenesis and angiogenesis capacity in Ishikawa endometrial cancer cells. To this end, cells were exposed to different energy densities (fluences) of 4, 8, 16, 32, and 64 J/cm2 for 5 days (once every 24 h), and cell viability was determined using an MTT assay. Based on data from the MTT panel, cells were exposed to 4 and 16 J/cm2 for subsequent analyses. Exosome biogenesis was also monitored via monitoring the expression of CD63, ALIX, and Rab27a and b. The size and morphology of exosomes in the supernatant were measured using scanning electron microscopy (SEM), and dynamic light scattering (DLS). Using Transwell insert, the migration capacity of these cells was studied. The angiogenic effects of irradiated Ishikawa cell secretome at different fluences were monitored on human endothelial cells using in vitro tubulogenesis. Results indicated LED can reduce the viability of Ishikawa cells in a dose-dependent manner. According to our data, 4 and 64 J/cm2 groups exhibited minimum and maximum cytotoxic effects compared to the control cells. Data revealed a close proportional relationship between the power of laser and exosome average size compared to the non-treated control cells (p < 0.05). Real-time PCR analysis showed the suppression of Rab27b and up-regulation of Rab27a in irradiated cells exposed to 4 and 16 J/cm2 (p < 0.05). These effects were evident in the 16 J/cm2 group. Likewise, LED can inhibit the migration of Ishikawa cells in a dose-dependent manner (p < 0.05). Tubulogenesis activity of endothelial cells was suppressed after incubation with the secretome of irradiated Ishikawa cells (p < 0.05). These data showed tumoricidal properties of LED irradiation on human adenocarcinoma Ishikawa cells via the inhibition of exosome biogenesis and suppression of angiogenesis capacity.
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Adenocarcinoma , Exossomos , Sobrevivência Celular/efeitos da radiação , Células Endoteliais , Exossomos/metabolismo , Feminino , Humanos , Regulação para CimaRESUMO
Tumor cells actively release large quantities of exosomes, which pivotally participate in the regulation of cancer biology, including head and neck cancer (HNC). Exosome biogenesis and release are complex and elaborate processes that are considered to be similar to the process of exocyst-mediated vesicle delivery. By analyzing the expression of exocyst subunits and their role in patients with HNC, we aimed to identify exocyst and its functions in exosome biogenesis and investigate the molecular mechanisms underlying the regulation of exosome transport in HNC cells. We observed that exocysts were highly expressed in HNC cells and could promote exosome secretion in these cells. In addition, downregulation of exocyst expression inhibited HN4 cell proliferation by reducing exosome secretion. Interestingly, immunofluorescence and electron microscopy revealed the accumulation of multivesicular bodies (MVBs) after the knockdown of exocyst. Autophagy, the major pathway of exosome degradation, is not activated by this intracellular accumulation of MVBs, but these MVBs are consumed when autophagy is activated under the condition of cell starvation. Rab11a, a small GTPase that is involved in MVB fusion, also interacted with the exocyst. These findings suggest that the exocyst can regulate exosome biogenesis and participate in the malignant behavior of tumor cells.
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During the last two decades, melatonin has been found to have pleiotropic effects via different mechanisms on its target cells. Data are abundant for some aspects of the signaling pathways within cells while other casual mechanisms have not been adequately addressed. From an evolutionary perspective, eukaryotic cells are equipped with a set of interrelated endomembrane systems consisting of intracellular organelles and secretory vesicles. Of these, exosomes are touted as cargo-laden secretory vesicles that originate from the endosomal multivesicular machinery which participate in a mutual cross-talk at different cellular interfaces. It has been documented that cells transfer various biomolecules and genetic elements through exosomes to sites remote from the original cell in a paracrine manner. Findings related to the molecular mechanisms between melatonin and exosomal biogenesis and cargo sorting are the subject of the current review. The clarification of the interplay between melatonin and exosome biogenesis and cargo sorting at the molecular level will help to define a cell's secretion capacity. This review precisely addresses the role and potential significance of melatonin in determining the efflux capacity of cells via the exosomal pathway. Certain cells, for example, stem cells actively increase exosome efflux in response to melatonin treatment which accelerates tissue regeneration after transplantation into the injured sites.
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BACKGROUND: The recent studies highlighted the critical role of exosomes in the regulation of inflammation. Here, we investigated the dynamic biogenesis of the exosomes in the rat model of asthma. RESULTS: Our finding showed an increase in the expression of IL-4 and the suppression of IL-10 in asthmatic lung tissues compared to the control samples (p < 0.05). Along with the promotion of IL-4, the protein level of TNF-α was induced, showing an active inflammatory status in OVA-sensitized rats. According to our data, the promotion of asthmatic responses increased exosome biogenesis indicated by increased CD63 levels and acetylcholine esterase activity compared to the normal condition (p < 0.05). CONCLUSION: Data suggest that the stimulation of inflammatory response in asthmatic rats could simultaneously increase the paracrine activity of pulmonary cells via the exosome biogenesis. Exosome biogenesis may correlate with the inflammatory response.
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As the recognition between natural killer (NK) cells and cancer cells does not require antigen presentation, NK cells are being actively studied for use in adoptive cell therapies in the rapidly evolving armamentarium of cancer immunotherapy. In addition to utilizing NK cells, recent studies have shown that exosomes derived from NK cells also exhibit antitumor properties. Furthermore, these NK cell-derived exosomes exhibit higher stability, greater modification potentials and less immunogenicity compared to NK cells. Therefore, technologies that allow highly sensitive and specific isolation of NK cells and NK cell-derived exosomes can enable personalized NK-mediated cancer therapeutics in the future. Here, a novel microfluidic system to collect patient-specific NK cells and on-chip biogenesis of NK-exosomes is proposed. In a small cohort of non-small cell lung cancer (NSCLC) patients, both NK cells and circulating tumor cells (CTCs) were isolated, and it is found NSCLC patients have high numbers of NK and NK-exosomes compared with healthy donors, and these concentrations show a trend of positive and negative correlations with bloodborne CTC numbers, respectively. It is further demonstrated that the NK-exosomes harvested from NK-graphene oxide chip exhibit cytotoxic effect on CTCs. This versatile system is expected to be used for patient-specific NK-based immunotherapies along with CTCs for potential prognostic/diagnostic applications.
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Neuroblastoma is a solid tumor (a lump or mass), often found in the small glands on top of the kidneys, and most commonly affects infants and young children. Among neuroblastomas, high-risk neuroblastomas are very aggressive and resistant to most kinds of intensive treatment. Immunotherapy, which uses the immune system to fight against cancer, has shown great promise in treating many types of cancer. However, high-risk neuroblastoma is often resistant to this approach as well. Recent studies revealed that small vesicles known as exosomes, which are envelopes, could deliver a cargo of small RNA molecules and provide communication between neuroblastoma cells and the surrounding cells and trigger metastasis and resistance to immunotherapy. In this chapter, we describe the role of exosomes and small RNA molecules in the metastasis and regression of neuroblastoma and the potential therapeutic approaches to combat this menace.
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Resistencia a Medicamentos Antineoplásicos , Exossomos , Neuroblastoma , Criança , Pré-Escolar , Exossomos/genética , Humanos , Imunoterapia , Neuroblastoma/genética , Neuroblastoma/terapiaRESUMO
Exosomes are the most researched extracellular vesicles. In many biological, physiological, and pathological studies, they have been identified as suitable candidates for treatment and diagnosis of diseases by acting as the carriers of both drugs and genes. Considerable success has been achieved regarding the use of exosomes for tissue regeneration, cancer diagnosis, and targeted drug/gene delivery to specific tissues. While major progress has been made in exosome extraction and purification, extraction of large quantities of exosomes is still a major challenge. This issue limits the scope of both exosome-based research and therapeutic development. In this review, we have aimed to summarize experimental studies focused at increasing the number of exosomes. Biotechnological studies aimed at identifying the pathways of exosome biogenesis to manipulate some genes in order to increase the production of exosomes. Generally, two major strategies are employed to increase the production of exosomes. First, oogenesis pathways are genetically manipulated to overexpress activator genes of exosome biogenesis and downregulate the genes involved in exosome recycling pathways. Second, manipulation of the cell culture medium, treatment with specific drugs, and limiting certain conditions can force the cell to produce more exosomes. In this study, we have reviewed and categorized these strategies. It is hoped that the information presented in this review will provide a better understanding for expanding biotechnological approaches in exosome-based therapeutic development.
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Biotecnologia , Exossomos/metabolismo , Exossomos/genética , Engenharia Genética , Engenharia Metabólica , Redes e Vias Metabólicas , ProteômicaRESUMO
The abnormal deposition of proteins in brain tissue is a common feature of neurodegenerative diseases (NDs) often accompanied by the spread of mutated proteins, causing neuronal toxicity. Exosomes play a fundamental role on their releasing in extracellular space after endosomal pathway activation, allowing to remove protein aggregates by lysosomal degradation or their inclusion into multivesicular bodies (MVBs), besides promoting cellular cross-talk. The emerging evidence of pathogenic mutations associated to ND susceptibility, leading to impairment of exosome production and secretion, opens a new perspective on the mechanisms involved in neurodegeneration. Recent findings suggest to investigate the genetic mechanisms regulating the different exosome functions in central nervous system (CNS), to understand their role in the pathogenesis of NDs, addressing the identification of diagnostic and pharmacological targets. This review aims to summarize the mechanisms underlying exosome biogenesis, their molecular composition and functions in CNS, with a specific focus on the recent findings invoking a defective exosome biogenesis as a common biological feature of the major NDs, caused by genetic alterations. Further definition of the consequences of specific genetic mutations on exosome biogenesis and release will improve diagnostic and pharmacological studies in NDs.
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Suscetibilidade a Doenças , Exossomos/metabolismo , Variação Genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Animais , Biomarcadores , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Doenças Neurodegenerativas/patologiaRESUMO
Syntenin is an adaptor-like molecule that has two adjacent tandem postsynaptic density protein 95/Discs large protein/Zonula occludens 1 (PDZ) domains. The PDZ domains of syntenin recognize multiple peptide motifs with low to moderate affinity. Many reports have indicated interactions between syntenin and a plethora of proteins. Through interactions with various proteins, syntenin regulates the architecture of the cell membrane. As a result, increases in syntenin levels induce the metastasis of tumor cells, protrusion along the neurite in neuronal cells, and exosome biogenesis in various cell types. Here, we review the updated data that support various roles for syntenin in the regulation of neuronal synapses, tumor cell invasion, and exosome control.