Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3.
Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3.
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在脊椎动下共济失调中，与疾病相关的少突胶质细胞特征在3型脊髓脊髓性共济失调中处于空间失调。
DOI：
10.3389/fnins.2023.1118429
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发表时间：
2023
影响因子：
4.3
通讯作者：
McLoughlin, Hayley S.
中科院分区：
文献类型：
--
作者：
Schuster, Kristen H.;DiFranco, Danielle M.;Putka, Alexandra F.;Mato, Juan P.;Jarrah, Sabrina I.;Stec, Nicholas R.;Sundararajan, Vikram O.;McLoughlin, Hayley S.
脊髓小脑型共济失调3型(SCA3)是由ATXN3基因CAG重复扩增引起的一种神经退行性疾病。虽然ATXN3蛋白在整个中枢神经系统中普遍表达，但SCA3患者的局部病理在选定的神经元群体中观察到，最近在富含少突胶质细胞的白质束中观察到。我们以前在SCA3过度表达的小鼠模型中总结了这些白质异常，并证明少突胶质细胞成熟损伤是SCA3发病机制中最早和最进行性的变化之一。最近，疾病相关的少突胶质细胞签名已成为其他几种神经退行性疾病的重要贡献者，包括阿尔茨海默病、亨廷顿病和帕金森病，但它们在区域脆弱性和疾病进展中的作用仍未被探索。在这里，我们是第一个以区域依赖的方式比较评估人类组织中髓鞘形成的人。将这些发现转化到SCA3小鼠的疾病模型中，我们证实了突变Atxn3的内源性表达导致了SCA3敲入模型中少突胶质细胞成熟标志的局部转录失调。然后，我们研究了在过度表达SCA3小鼠模型中成熟少突胶质细胞转录失调的时空进程，以及它与运动障碍的发生之间的关系。我们进一步确定，随着时间的推移，SCA3小鼠成熟少突胶质细胞数量的区域性减少与SCA3患者脑萎缩的发生和发展平行。这项工作强调了疾病相关的少突胶质细胞特征对区域脆弱性的预期贡献，并可能为几种神经退行性疾病的生物标记物评估和治疗干预所必需的时间点和靶区提供信息。
Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by a CAG repeat expansion in the ATXN3 gene. Though the ATXN3 protein is expressed ubiquitously throughout the CNS, regional pathology in SCA3 patients is observed within select neuronal populations and more recently within oligodendrocyte-rich white matter tracts. We have previously recapitulated these white matter abnormalities in an overexpression mouse model of SCA3 and demonstrated that oligodendrocyte maturation impairments are one of the earliest and most progressive changes in SCA3 pathogenesis. Disease-associated oligodendrocyte signatures have recently emerged as significant contributors to several other neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, but their role in regional vulnerability and disease progression remains unexplored. Here, we are the first to comparatively assess myelination in human tissue in a region-dependent manner. Translating these findings to SCA3 mouse models of disease, we confirmed endogenous expression of mutant Atxn3 leads to regional transcriptional dysregulation of oligodendrocyte maturation markers in Knock-In models of SCA3. We then investigated the spatiotemporal progression of mature oligodendrocyte transcriptional dysregulation in an overexpression SCA3 mouse model and how it relates to the onset of motor impairment. We further determined that regional reduction in mature oligodendrocyte cell counts in SCA3 mice over time parallels the onset and progression of brain atrophy in SCA3 patients. This work emphasizes the prospective contributions of disease-associated oligodendrocyte signatures to regional vulnerability and could inform timepoints and target regions imperative for biomarker assessment and therapeutic intervention in several neurodegenerative diseases.
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影响因子：
25
作者：
Kenigsbuch, Mor;Bost, Pierre;Halevi, Shahar;Chang, Yuzhou;Chen, Shuo;Ma, Qin;Hajbi, Renana;Schwikowski, Benno;Bodenmiller, Bernd;Fu, Hongjun;Schwartz, Michal;Amit, Ido
通讯作者：
Amit, Ido
影响因子：
25
作者：
Fu H;Hardy J;Duff KE
通讯作者：
Duff KE
影响因子：
11
作者：
Hobbs, Nicola Z.;Henley, Susie M. D.;Tabrizi, Sarah J.
通讯作者：
Tabrizi, Sarah J.
影响因子：
2.4
作者：
D'Abreu, Anelyssa;Franca, Marcondes C., Jr.;Cendes, Fernando
通讯作者：
Cendes, Fernando
影响因子：
5.1
作者：
Haas E;Incebacak RD;Hentrich T;Huridou C;Schmidt T;Casadei N;Maringer Y;Bahl C;Zimmermann F;Mills JD;Aronica E;Riess O;Schulze-Hentrich JM;Hübener-Schmid J
通讯作者：
Hübener-Schmid J