与脱髓鞘疾病活动相关的血液外泌体连接蛋白和小RNA

Blood exosome connexins and small RNAs related to demyelinating disease activity.

作者信息

Maimaitijiang Guzailiayi, Kira Jun-Ichi, Nakamura Yuri, Watanabe Mitsuru, Takase Ezgi Ozdemir, Nagata Satoshi, Sakoda Ayako, Zhang Xu, Masaki Katsuhisa, Yamasaki Ryo, Isobe Noriko, Yamaguchi Hiroo, Imamura Tomohiro

机构信息

Translational Neuroscience Research Center, Graduate School of Medicine, International University of Health and Welfare, Okawa, Japan.

Department of Neurology, Brain and Nerve Center, Fukuoka Central Hospital, International University of Health and Welfare, Fukuoka, Japan.

出版信息

Ann Clin Transl Neurol. 2025 Mar;12(3):538-555. doi: 10.1002/acn3.52307. Epub 2025 Feb 3.

DOI:10.1002/acn3.52307

PMID:39901658

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11920735/

Abstract

OBJECTIVES

To assess blood exosome (Ex)-connexin (Cx)43 (encoded by GJA1) and its truncated isoforms in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), which show distinct alterations in astroglial Cx43.

METHODS

Serum Exs from 48 patients with MS (34 relapsing-remitting, 14 secondary-progressive), 35 with NMOSD, 20 with other inflammatory neurologic diseases (OIND), and 17 healthy controls (HC) were subjected to quantitative Western blotting for Cx43, single-molecule array for neurofilament-L, and quantitative polymerase chain reaction for non-coding RNAs detected by RNA sequencing. Sera from control and astroglia-specific Cx43 inducible conditional knockout (Cx43-icKO) mice with experimental autoimmune encephalomyelitis (EAE) were also tested.

RESULTS

Ex-GJA1-29k was markedly higher in MS than in NMOSD, OIND, and HC; it successively increased at relapse, remission, and secondary progression, and positively correlated with disability scores. Ex-hsa-miR-133b and other hsa-miRs that bind to full-length Cx43 were significantly lower in secondary-progressive MS than in HC, and Ex-hsa-miR-133b was negatively correlated with disability scores. Ex-GJA1-11k expression was lower in NMOSD at relapse than in HC and OIND, and was negatively correlated with disability score worsening and Ex-neurofilament-L levels. NMOSD at relapse had significantly higher expression of small nucleolar RNA (SNORD37, SNORD95, and SNORD97) than HC, and SNORD37 and SNORD95 showed strong negative correlations with disability scores. Control mice showed increased Ex-GJA1-43k and -29k during EAE; this effect was markedly reduced in Cx43-icKO mice with attenuated EAE.

INTERPRETATION

Blood Ex-Cx43-truncated isoforms and small non-coding RNAs, which partially come from brain astroglia, are distinctly dysregulated in MS and NMSOD.

摘要

目的

评估多发性硬化症（MS）和视神经脊髓炎谱系障碍（NMOSD）患者血液中的外泌体（Ex）-连接蛋白（Cx）43（由GJA1编码）及其截短异构体，这些疾病在星形胶质细胞Cx43中表现出明显改变。

方法

对48例MS患者（34例复发缓解型、14例继发进展型）、35例NMOSD患者、20例其他炎症性神经系统疾病（OIND）患者及17名健康对照者（HC）的血清外泌体进行Cx43定量蛋白质免疫印迹、神经丝轻链单分子阵列分析以及通过RNA测序检测的非编码RNA的定量聚合酶链反应。还检测了实验性自身免疫性脑脊髓炎（EAE）对照小鼠和星形胶质细胞特异性Cx43诱导性条件敲除（Cx43-icKO）小鼠的血清。

结果

MS患者的Ex-GJA1-29k明显高于NMOSD、OIND患者及HC；在复发、缓解和继发进展期依次升高，且与残疾评分呈正相关。继发进展型MS患者的Ex-hsa-miR-133b和其他与全长Cx43结合的hsa-miRs明显低于HC，且Ex-hsa-miR-133b与残疾评分呈负相关。NMOSD复发期的Ex-GJA1-11k表达低于HC和OIND，且与残疾评分恶化及Ex-神经丝轻链水平呈负相关。NMOSD复发期的小核仁RNA（SNORD37、SNORD95和SNORD97）表达明显高于HC，且SNORD37和SNORD95与残疾评分呈强负相关。对照小鼠在EAE期间Ex-GJA1-43k和-29k增加；在EAE减轻的Cx43-icKO小鼠中这种效应明显降低。