Exosomes in Epilepsy of Tuberous Sclerosis Complex: Carriers of Pro-Inflammatory MicroRNAs

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

doi:10.3390/ncrna7030040

Exosomes in Epilepsy of Tuberous Sclerosis Complex: Carriers of Pro-Inflammatory MicroRNAs

Noncoding RNA. 2021 Jul 10;7(3):40. doi: 10.3390/ncrna7030040.

Authors

Daniela Cukovic¹, Shruti Bagla¹, Dylan Ukasik², Paul M Stemmer³, Bhanu P Jena⁴, Akshata R Naik⁴, Sandeep Sood⁵, Eishi Asano^{1

2

6}, Aimee Luat^{6

7}, Diane C Chugani⁸, Alan A Dombkowski^{1

2}

Affiliations

¹ Department of Pediatrics, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
² Translational Neurosciences Program, Wayne State University, Detroit, MI 48201, USA.
³ Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48201, USA.
⁴ Department of Physiology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
⁵ Department of Neurosurgery, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
⁶ Department of Neurology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
⁷ Department of Pediatrics, Central Michigan University, Mt Pleasant, MI 48858, USA.
⁸ Departments of Communication Sciences and Disorders, and Chemistry and Biochemistry, University of Delaware, Newark, DE 19713, USA.

Abstract

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 SQSTM1 (p62) and CDKN1A (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.

Keywords: epilepsy; exosome; microRNA; neuroinflammation; toll-like receptor; tuberous sclerosis complex.

Abstract

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