Abstract
Exosomes can pass through the blood-brain barrier and are present in the cerebrospinal fluid (CSF). The components in exosomes, such as DNA, RNA, protein, and lipids, change greatly and are closely related to disease progression. Circular RNA (circRNA) is stable in structure and has a long half-life in exosomes without degradation. Therefore, circRNA is considered an ideal biomarker and can be used to monitor a variety of central nervous system diseases. This study aimed to investigate the expression profiles of exosomal circRNA (exo-circRNA) in CSF from patients with immune-mediated demyelinating diseases to identify suitable biomarkers for the early diagnosis of immune-mediated demyelinating diseases. circRNA expression levels in exosomes obtained from five CSF samples from immune-mediated demyelinating disease patients and five paired CSF control samples were analyzed using a hybridization array. Hierarchical clustering analysis showed that 5,095 exo-circRNAs were differentially expressed between patients with immune-mediated demyelinating diseases and paired control samples. Of these exo-circRNAs, 26 were identified as significantly differentially expressed in CSF exosomes from patients with immune-mediated demyelinating diseases (FC ≥1.5 and p ≤ 0.05). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that the upregulation or activation of protein tyrosine phosphatase receptor type F (PTPRF) and RAD23 homolog B, nucleotide excision repair protein (RAD23B) may be associated with the occurrence and development of immune-mediated demyelinating diseases. Then, a competing endogenous RNA network was constructed and centered on the most upregulated/downregulated exo-circRNAs to predict their function in immune-mediated demyelinating diseases. In addition, reverse transcription quantitative polymerase chain reaction results stating that hsa_circ_0087862 and hsa_circ_0012077 were validated in an independent cohort of subjects. Canonical correlation analysis results indicated a potential connection between exosomal hsa_circ_0012077 expression level and immunoglobulin G levels in CSF. Finally, the receiver operating characteristic (ROC) curve showed that when hsa_circ_0087862 or hsa_circ_0012077 was employed alone for diagnosing immune-mediated demyelinating diseases, the diagnostic accuracy was 100%. In conclusion, based on this study, exosomal hsa_circ_0087862 and hsa_circ_0012077 in CSF could be used as suitable biomarkers for the diagnosis of immune-mediated demyelinating disease based on their expression levels. Moreover, the upregulation or activation of PTPRF and RAD23B was potentially associated with the occurrence and development of immune-mediated demyelinating diseases.
Highlights
Demyelinating diseases are acquired diseases with varying etiologies and clinical manifestations but similar clinical characteristics (Hoftberger and Lassmann, 2017)
This result indicated that the quantity of RNA extracted from exosomes was sufficient for molecular exo-Circular RNA (circRNA) as Biomarker of Immune-Mediated Demyelinating Disease detection techniques, such as RNA array analysis, RNA of these differentially expressed exo-circRNAs are listed in sequencing, and reverse transcription quantitative polymerase chain reaction (RT-qPCR)
We investigated the exo-circRNA expression profiles in cerebrospinal fluid (CSF) of patients with immune-mediated demyelinating diseases
Summary
Demyelinating diseases are acquired diseases with varying etiologies and clinical manifestations but similar clinical characteristics (Hoftberger and Lassmann, 2017). The main causes are as follows: 1, immune-mediated disorders, such as multiple sclerosis (MS) and acute infective polyradicular neuritis ( known as Guillain-Barré syndrome, GBS); 2, viral infection, such as progressive multifocal leukoencephalitis and subacute sclerosing panencephalitis; 3, nutritional disorders, such as central pontine myelin disintegration; and 4, hypoxia, such as delayed hypoxic demyelinating encephalopathy and progressive subcortical ischemic encephalopathy (Matute-Blanch et al, 2017). In China, the main treatments in the early stages of immune-mediated demyelinating diseases are hormones and nutritional therapy (Neuroimmunity Branch of Chinese Society of Immunology and Neuroimmunology Group, 2018). In chronic demyelinating diseases, repeated demyelination and remyelination result in significant proliferation of Schwann cells, thickening of nerve fibers, and loss of axons, which may lead to incomplete recovery of nerve function (Khoo et al, 2019).
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