Pathogenetic Mechanisms Underlying Spinocerebellar Ataxia Type 3 Are Altered in Primary Oligodendrocyte Culture.
Pathogenetic Mechanisms Underlying Spinocerebellar Ataxia Type 3 Are Altered in Primary Oligodendrocyte Culture.
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作者：
新出现的证据表明，非神经元细胞，特别是少突胶质细胞，参与了许多神经退行性疾病的病理生理学，包括阿尔茨海默病、帕金森病、肌萎缩侧索硬化、亨廷顿病和脊髓小脑共济失调3型（SCA 3）。我们最近证明，少突胶质细胞成熟的细胞自主功能障碍是SCA 3小鼠大脑脆弱区域最早和最强大的变化之一。然而，少突胶质细胞功能障碍的细胞和疾病特异性机制仍然知之甚少，难以在体内分离。在这项研究中，我们使用原代少突胶质细胞培养物来确定已知的致病性SCA 3机制如何影响这种细胞类型。我们从5- 7天大的小鼠中分离出少突胶质细胞祖细胞，这些小鼠过度表达人类突变体ATXN 3或缺乏小鼠ATXN 3，并在体外将它们分化长达5天。利用免疫细胞化学，我们的特点的贡献ATXN 3毒性获得的功能和功能丧失的少突胶质细胞成熟，蛋白质质量的途径，DNA损伤信号和甲基化状态。我们举例说明了初级少突胶质细胞培养物用于阐明与SCA 3相关的细胞特异性通路失调的效用。鉴于最近的工作表明，在其他神经退行性疾病的疾病相关的少突胶质细胞的签名，这种新的模型具有广泛的适用性，揭示少突胶质细胞的发病机制的贡献机制的见解。
Emerging evidence has implicated non-neuronal cells, particularly oligodendrocytes, in the pathophysiology of many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Spinocerebellar ataxia type 3 (SCA3). We recently demonstrated that cell-autonomous dysfunction of oligodendrocyte maturation is one of the of the earliest and most robust changes in vulnerable regions of the SCA3 mouse brain. However, the cell- and disease-specific mechanisms that underlie oligodendrocyte dysfunction remain poorly understood and are difficult to isolate in vivo. In this study, we used primary oligodendrocyte cultures to determine how known pathogenic SCA3 mechanisms affect this cell type. We isolated oligodendrocyte progenitor cells from 5- to 7-day-old mice that overexpress human mutant ATXN3 or lack mouse ATXN3 and differentiated them for up to 5 days in vitro. Utilizing immunocytochemistry, we characterized the contributions of ATXN3 toxic gain-of-function and loss-of-function in oligodendrocyte maturation, protein quality pathways, DNA damage signaling, and methylation status. We illustrate the utility of primary oligodendrocyte culture for elucidating cell-specific pathway dysregulation relevant to SCA3. Given recent work demonstrating disease-associated oligodendrocyte signatures in other neurodegenerative diseases, this novel model has broad applicability in revealing mechanistic insights of oligodendrocyte contribution to pathogenesis.
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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
影响因子：
12.7
作者：
Guo T;Noble W;Hanger DP
通讯作者：
Hanger DP
影响因子：
4.2
作者：
French, Heather Morein;Reid, Mary;Mamontov, Polina;Simmons, Rebecca A.;Grinspan, Judith B.
通讯作者：
Grinspan, Judith B.
DOI：
10.1002/mds.28140
发表时间：
2020-10
期刊：
Movement disorders : official journal of the Movement Disorder Society
影响因子：
--
作者：
Costa MDC;Radzwion M;McLoughlin HS;Ashraf NS;Fischer S;Shakkottai VG;Maciel P;Paulson HL;Öz G
通讯作者：
Öz G
影响因子：
6.7
作者：
Costa, Maria do Carmo;Paulson, Henry L.
通讯作者：
Paulson, Henry L.