Talukdar Gourango, Duvick Lisa, Yang Praseuth, O'Callaghan Brennon, Fuchs Gavin J, Cvetanovic Marija, Orr Harry T
University of Minnesota.
Res Sq. 2025 Apr 14:rs.3.rs-5664390. doi: 10.21203/rs.3.rs-5664390/v1.
Ataxin-1 (ATXN1) is a protein in which expansion of its polyglutamine tract causes the neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1) via a gain-of-function. Wild type ATXN1 was recently shown to have a protective role in regulating severity of experimental autoimmune encephalomyelitis (EAE), a well-established mouse model for Multiple sclerosis (MS). This study further investigates the role of ATXN1 with an expanded polyglutamine tract in the context of MS using an EAE mouse model.
Hemizygous ) mice or - , heterozygous mice that have one copy of the endogenous mouse gene replaced with a polyQ expanded pathogenic human gene, were injected with myelin oligodendrocytes glycoprotein (MOG) peptide to induce EAE. Immunohistochemical and biochemical approaches were used to analyze the degree of demyelination, cell loss, axonal degeneration as well as detecting the activated immune cells and inflammatory cytokines upon EAE induction in and - mice.
Our findings reveal that a loss-of-function of wild type in and mice significantly exacerbates the EAE symptoms, leading to increased demyelination, oligodendrocytes loss, heightened axon degeneration, and greater clinical disability in affected mice. Importantly, the data reveals that neurotoxic astrocytes are activated at acute stage of disease (PID-14) and at the chronic stage of disease (PID-30) neurotoxic astrocytes no longer show signs of activation. The data also demonstrated enhanced infiltration of immune cells into the lesions of mutant mice.
These results indicate that ATXN1 plays a protective role in modulating immune responses and maintaining neural integrity during MS. Importantly, expansion of the polyQ tract in ATXN1 results in a loss-of-function in ATXN1's ability to dampen the immune response. Understanding the functional role of ATXN1 in MS pathogenesis may open new avenues for therapeutic strategies aimed at mitigating disease progression.
ataxin-1（ATXN1）是一种蛋白质，其多聚谷氨酰胺序列的扩增通过功能获得导致神经退行性疾病1型脊髓小脑共济失调（SCA1）。野生型ATXN1最近被证明在调节实验性自身免疫性脑脊髓炎（EAE）的严重程度方面具有保护作用，EAE是一种成熟的多发性硬化症（MS）小鼠模型。本研究使用EAE小鼠模型进一步研究在MS背景下具有扩增多聚谷氨酰胺序列的ATXN1的作用。
将半合子（）小鼠或-，即一个内源性小鼠基因拷贝被多聚谷氨酰胺扩增的致病性人类基因取代的杂合子小鼠，注射髓鞘少突胶质细胞糖蛋白（MOG）肽以诱导EAE。采用免疫组织化学和生化方法分析脱髓鞘程度、细胞丢失、轴突变性，并检测和-小鼠在诱导EAE后活化的免疫细胞和炎性细胞因子。
我们的研究结果表明，和小鼠中野生型的功能丧失显著加重了EAE症状，导致脱髓鞘增加、少突胶质细胞丢失、轴突变性加剧，以及受影响小鼠的临床残疾程度加重。重要的是，数据显示神经毒性星形胶质细胞在疾病急性期（发病后天数-14）被激活，而在疾病慢性期（发病后天数-30）神经毒性星形胶质细胞不再显示激活迹象。数据还表明免疫细胞向突变小鼠病变部位的浸润增强。
这些结果表明，ATXN1在MS期间调节免疫反应和维持神经完整性方面发挥保护作用。重要的是，ATXN1中多聚谷氨酰胺序列的扩增导致ATXN1抑制免疫反应的能力丧失。了解ATXN1在MS发病机制中的功能作用可能为旨在减轻疾病进展的治疗策略开辟新途径。
