Exosomes in Epilepsy of Tuberous Sclerosis Complex: Carriers of Pro-Inflammatory MicroRNAs
Exosomes are a class of small, secreted extracellular vesicles (EV) that have recently gained considerable attention for their role in normal cellular function, disease processes and potential as biomarkers. Exosomes serve as intercellular messengers and carry molecular cargo that can alter gene exp...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-07-01
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| Series: | Non-Coding RNA |
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| Online Access: | https://www.mdpi.com/2311-553X/7/3/40 |
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| author | Daniela Cukovic Shruti Bagla Dylan Ukasik Paul M. Stemmer Bhanu P. Jena Akshata R. Naik Sandeep Sood Eishi Asano Aimee Luat Diane C. Chugani Alan A. Dombkowski |
| author_facet | Daniela Cukovic Shruti Bagla Dylan Ukasik Paul M. Stemmer Bhanu P. Jena Akshata R. Naik Sandeep Sood Eishi Asano Aimee Luat Diane C. Chugani Alan A. Dombkowski |
| author_sort | Daniela Cukovic |
| collection | DOAJ |
| description | Exosomes are a class of small, secreted extracellular vesicles (EV) that have recently gained considerable attention for their role in normal cellular function, disease processes and potential as biomarkers. Exosomes serve as intercellular messengers and carry molecular cargo that can alter gene expression and the phenotype of recipient cells. Here, we investigated alterations of microRNA cargo in exosomes secreted by epileptogenic tissue in tuberous sclerosis complex (TSC), a multi-system genetic disorder that includes brain lesions known as tubers. Approximately 90% of TSC patients suffer from seizures that originate from tubers, and ~60% are resistant to antiseizure drugs. It is unknown why some tubers cause seizures while others do not, and the molecular basis of drug-resistant epilepsy is not well understood. It is believed that neuroinflammation is involved, and characterization of this mechanism may be key to disrupting the “vicious cycle” between seizures, neuroinflammation, and increased seizure susceptibility. We isolated exosomes from epileptogenic and non-epileptogenic TSC tubers, and we identified differences in their microRNA cargo using small RNA-seq. We identified 12 microRNAs (including miR-142-3p, miR-223-3p and miR-21-5p) that are significantly increased in epileptogenic tubers and contain nucleic acid motifs that activate toll-like receptors (TLR7/8), initiating a neuroinflammatory cascade. Exosomes from epileptogenic tissue caused induction of key pathways in cultured cells, including innate immune signaling (TLR), inflammatory response and key signaling nodes <i>SQSTM1</i> (p62) and <i>CDKN1A</i> (p21). Genes induced in vitro were also significantly upregulated in epileptogenic tissue. These results provide new evidence on the role of exosomes and non-coding RNA cargo in the neuroinflammatory cascade of epilepsy and may help advance the development of novel biomarkers and therapeutic approaches for the treatment of drug-resistant epilepsy. |
| first_indexed | 2024-03-10T07:20:59Z |
| format | Article |
| id | doaj.art-23e20f1469964a0c82388b1a05e4dd68 |
| institution | Directory Open Access Journal |
| issn | 2311-553X |
| language | English |
| last_indexed | 2024-03-10T07:20:59Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Non-Coding RNA |
| spelling | doaj.art-23e20f1469964a0c82388b1a05e4dd682023-11-22T14:33:03ZengMDPI AGNon-Coding RNA2311-553X2021-07-01734010.3390/ncrna7030040Exosomes in Epilepsy of Tuberous Sclerosis Complex: Carriers of Pro-Inflammatory MicroRNAsDaniela Cukovic0Shruti Bagla1Dylan Ukasik2Paul M. Stemmer3Bhanu P. Jena4Akshata R. Naik5Sandeep Sood6Eishi Asano7Aimee Luat8Diane C. Chugani9Alan A. Dombkowski10Department of Pediatrics, School of Medicine, Wayne State University, Detroit, MI 48201, USADepartment of Pediatrics, School of Medicine, Wayne State University, Detroit, MI 48201, USATranslational Neurosciences Program, Wayne State University, Detroit, MI 48201, USAInstitute of Environmental Health Sciences, Wayne State University, Detroit, MI 48201, USADepartment of Physiology, School of Medicine, Wayne State University, Detroit, MI 48201, USADepartment of Physiology, School of Medicine, Wayne State University, Detroit, MI 48201, USADepartment of Neurosurgery, School of Medicine, Wayne State University, Detroit, MI 48201, USADepartment of Pediatrics, School of Medicine, Wayne State University, Detroit, MI 48201, USADepartment of Neurology, School of Medicine, Wayne State University, Detroit, MI 48201, USADepartments of Communication Sciences and Disorders, and Chemistry and Biochemistry, University of Delaware, Newark, DE 19713, USADepartment of Pediatrics, School of Medicine, Wayne State University, Detroit, MI 48201, USAExosomes are a class of small, secreted extracellular vesicles (EV) that have recently gained considerable attention for their role in normal cellular function, disease processes and potential as biomarkers. Exosomes serve as intercellular messengers and carry molecular cargo that can alter gene expression and the phenotype of recipient cells. Here, we investigated alterations of microRNA cargo in exosomes secreted by epileptogenic tissue in tuberous sclerosis complex (TSC), a multi-system genetic disorder that includes brain lesions known as tubers. Approximately 90% of TSC patients suffer from seizures that originate from tubers, and ~60% are resistant to antiseizure drugs. It is unknown why some tubers cause seizures while others do not, and the molecular basis of drug-resistant epilepsy is not well understood. It is believed that neuroinflammation is involved, and characterization of this mechanism may be key to disrupting the “vicious cycle” between seizures, neuroinflammation, and increased seizure susceptibility. We isolated exosomes from epileptogenic and non-epileptogenic TSC tubers, and we identified differences in their microRNA cargo using small RNA-seq. We identified 12 microRNAs (including miR-142-3p, miR-223-3p and miR-21-5p) that are significantly increased in epileptogenic tubers and contain nucleic acid motifs that activate toll-like receptors (TLR7/8), initiating a neuroinflammatory cascade. Exosomes from epileptogenic tissue caused induction of key pathways in cultured cells, including innate immune signaling (TLR), inflammatory response and key signaling nodes <i>SQSTM1</i> (p62) and <i>CDKN1A</i> (p21). Genes induced in vitro were also significantly upregulated in epileptogenic tissue. These results provide new evidence on the role of exosomes and non-coding RNA cargo in the neuroinflammatory cascade of epilepsy and may help advance the development of novel biomarkers and therapeutic approaches for the treatment of drug-resistant epilepsy.https://www.mdpi.com/2311-553X/7/3/40microRNAexosomeepilepsytuberous sclerosis complexneuroinflammationtoll-like receptor |
| spellingShingle | Daniela Cukovic Shruti Bagla Dylan Ukasik Paul M. Stemmer Bhanu P. Jena Akshata R. Naik Sandeep Sood Eishi Asano Aimee Luat Diane C. Chugani Alan A. Dombkowski Exosomes in Epilepsy of Tuberous Sclerosis Complex: Carriers of Pro-Inflammatory MicroRNAs Non-Coding RNA microRNA exosome epilepsy tuberous sclerosis complex neuroinflammation toll-like receptor |
| title | Exosomes in Epilepsy of Tuberous Sclerosis Complex: Carriers of Pro-Inflammatory MicroRNAs |
| title_full | Exosomes in Epilepsy of Tuberous Sclerosis Complex: Carriers of Pro-Inflammatory MicroRNAs |
| title_fullStr | Exosomes in Epilepsy of Tuberous Sclerosis Complex: Carriers of Pro-Inflammatory MicroRNAs |
| title_full_unstemmed | Exosomes in Epilepsy of Tuberous Sclerosis Complex: Carriers of Pro-Inflammatory MicroRNAs |
| title_short | Exosomes in Epilepsy of Tuberous Sclerosis Complex: Carriers of Pro-Inflammatory MicroRNAs |
| title_sort | exosomes in epilepsy of tuberous sclerosis complex carriers of pro inflammatory micrornas |
| topic | microRNA exosome epilepsy tuberous sclerosis complex neuroinflammation toll-like receptor |
| url | https://www.mdpi.com/2311-553X/7/3/40 |
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