Engelenburg Hendrik J, van den Bosch Aletta M R, Chen J Q Alida, Hsiao Cheng-Chih, Melief Marie-José, Harroud Adil, Huitinga Inge, Hamann Jörg, Smolders Joost
Neuroimmunology Research Group, Netherlands Institute for Neuroscience, 1105 BA Amsterdam, the Netherlands.
MS Center ErasMS, Departments of Neurology and Immunology, Erasmus MC, University Medical Center Rotterdam, 3015 CN Rotterdam, the Netherlands.
iScience. 2025 Apr 15;28(5):112430. doi: 10.1016/j.isci.2025.112430. eCollection 2025 May 16.
The genetic variant rs10191329 has been identified to associate with faster disability accrual in multiple sclerosis (MS). We investigated the impact of rs10191329 carriership on MS pathology and flanking genes dysferlin () and zinc finger protein 638 () in the Netherlands Brain Bank cohort ( = 290) by comparing rs10191329 ( = 6) to matched rs10191329 carriers ( = 12). rs10191329 carriership associated with more acute axonal stress, reduced layer 2 neuronal density, and a higher proportion of lesions with foamy microglia. In rs10191329 donors, normal appearing white matter was characterized by a higher proportion of ZNF638 oligodendrocytes, and normal appearing gray matter showed more DYSF cells. Nuclear RNA sequencing showed an upregulation of mitochondrial genes in rs10191329 carriers. These data suggest that MS severity associates with an increased susceptibility to neurodegeneration and chronic inflammation. Understanding the role of DYSF, ZNF638, and mitochondrial pathways may reveal new therapeutic targets to attenuate MS progression.
基因变体rs10191329已被确定与多发性硬化症（MS）中更快的残疾累积相关。我们通过比较荷兰脑库队列（n = 290）中rs10191329非携带者（n = 6）与匹配的rs10191329携带者（n = 12），研究了rs10191329携带状态对MS病理学以及侧翼基因dysferlin（DYSF）和锌指蛋白638（ZNF638）的影响。rs10191329携带状态与更严重的轴突应激、2层神经元密度降低以及具有泡沫状小胶质细胞的病变比例更高相关。在rs10191329供体中，外观正常的白质的特征是ZNF638少突胶质细胞比例更高，外观正常的灰质显示更多DYSF细胞。核RNA测序显示rs10191329携带者中线粒体基因上调。这些数据表明，MS的严重程度与神经退行性变和慢性炎症易感性增加相关。了解DYSF、ZNF638和线粒体途径的作用可能会揭示减轻MS进展的新治疗靶点。
