Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model.
Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model.
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DOI：
10.1093/braincomms/fcab255
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发表时间：
2021
影响因子：
4.8
通讯作者：
Chandran S
中科院分区：
文献类型：
--
作者：
Barton SK;Magnani D;James OG;Livesey MR;Selvaraj BT;James OT;Perkins EM;Gregory JM;Cleary E;Ausems CRM;Carter RNC;Vasistha NA;Zhao C;Burr K;Story D;Cardinali A;Morton NM;Hardingham GE;Wyllie DJA;Chandran S
少突胶质细胞参与肌萎缩侧索硬化症的发病机制，并显示出反式反应DNA结合蛋白-43（TDP-43）病理性包涵体。为了研究TDP-43突变对人少突胶质细胞的细胞自主后果，我们从患者来源的诱导多能干细胞系中产生了少突胶质细胞，这些细胞系在TARDBP基因中含有突变，即G298 S和M337 V。通过免疫细胞化学，电生理评估通过全细胞膜片钳，和三维培养相结合，少突胶质细胞分化，成熟或髓鞘形成没有差异。此外，单羧酸转运蛋白1（乳酸转运蛋白）的表达分析加上糖酵解应激试验表明，没有赤字乳酸输出。然而，使用共聚焦显微镜，我们报告了TDP-43突变依赖性病理性TDP-43错误累积。此外，使用体外膜片钳记录，我们发现功能性钙渗透α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体在少突胶质细胞失调。总之，这些发现为进一步研究少突胶质细胞和细胞自主性在TDP-43蛋白病中的作用建立了一个平台。巴顿等人报道，来源于患者诱导的多能干细胞的少突胶质细胞在TARDBP基因中具有突变（这些突变是肌萎缩性侧索硬化症的病因），表现出内在功能障碍。与对照少突胶质细胞相比，它们具有致病性蛋白质积累以及改变的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体表达。
Oligodendrocytes are implicated in amyotrophic lateral sclerosis pathogenesis and display transactive response DNA-binding protein-43 (TDP-43) pathological inclusions. To investigate the cell autonomous consequences of TDP-43 mutations on human oligodendrocytes, we generated oligodendrocytes from patient-derived induced pluripotent stem cell lines harbouring mutations in the TARDBP gene, namely G298S and M337V. Through a combination of immunocytochemistry, electrophysiological assessment via whole-cell patch clamping, and three-dimensional cultures, no differences in oligodendrocyte differentiation, maturation or myelination were identified. Furthermore, expression analysis for monocarboxylate transporter 1 (a lactate transporter) coupled with a glycolytic stress test showed no deficit in lactate export. However, using confocal microscopy, we report TDP-43 mutation-dependent pathological mis-accumulation of TDP-43. Furthermore, using in vitro patch-clamp recordings, we identified functional Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor dysregulation in oligodendrocytes. Together, these findings establish a platform for further interrogation of the role of oligodendrocytes and cellular autonomy in TDP-43 proteinopathy. Barton et al. report that oligodendrocytes derived from patient-induced pluripotent stem cells that harbour mutations in the TARDBP gene (these mutations are causative of amyotrophic lateral sclerosis) exhibit intrinsic dysfunction. They harbour pathogenic protein accumulation as well as have altered α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor expression, compared to control oligodendrocytes.
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影响因子：
11.8
作者：
James OG;Selvaraj BT;Magnani D;Burr K;Connick P;Barton SK;Vasistha NA;Hampton DW;Story D;Smigiel R;Ploski R;Brophy PJ;Ffrench-Constant C;Lyons DA;Chandran S
通讯作者：
Chandran S
影响因子：
12.7
作者：
Ditsworth D;Maldonado M;McAlonis-Downes M;Sun S;Seelman A;Drenner K;Arnold E;Ling SC;Pizzo D;Ravits J;Cleveland DW;Da Cruz S
通讯作者：
Da Cruz S
DOI：
10.1073/pnas.1202922109
发表时间：
2012-04-10
影响因子：
11.1
作者：
Bilican, Bilada;Serio, Andrea;Chandran, Siddharthan
通讯作者：
Chandran, Siddharthan
影响因子：
25
作者：
Kang, Shin H.;Li, Ying;Fukaya, Masahiro;Lorenzini, Ileana;Cleveland, Don W.;Ostrow, Lyle W.;Rothstein, Jeffrey D.;Bergles, Dwight E.
通讯作者：
Bergles, Dwight E.
影响因子：
13.6
作者：
Evonuk, Kirsten S.;Doyle, Ryan E.;DeSilva, Tara M.
通讯作者：
DeSilva, Tara M.