CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson's disease.
CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson's disease.
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DOI：
10.1038/s41467-020-18689-x
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发表时间：
2020-09-28
影响因子：
16.6
通讯作者：
Wade-Martins R
中科院分区：
文献类型：
--
作者：
Bengoa-Vergniory N;Faggiani E;Ramos-Gonzalez P;Kirkiz E;Connor-Robson N;Brown LV;Siddique I;Li Z;Vingill S;Cioroch M;Cavaliere F;Threlfell S;Roberts B;Schrader T;Klärner FG;Cragg S;Dehay B;Bitan G;Matute C;Bezard E;Wade-Martins R
帕金森氏病(PD)影响全球数百万患者，其特征是多巴胺神经元中的α-突触核蛋白聚集。分子钳已显示出很高的潜在抗聚集剂，靶向淀粉样蛋白形成过程中带正电荷的残基。在这里，我们报告了CLR01分子钳减少了PD脑蛋白提取物处理的诱导多能干细胞来源的多巴胺能培养物的聚集和毒性。在微流控设备中，当轴突末端暴露于α-突触核蛋白寡聚体时，CLR01减少了细胞胞浆中α-突触核蛋白的聚集。然后，我们在人源化的α-突触核蛋白过度表达的小鼠模型中测试了CLR01；12个月大、运动缺陷较轻的小鼠表现出运动缺陷的改善和低聚α-突触核蛋白负荷的减少。最后，CLR01减少了将α-突触核蛋白聚集体注射到纹状体或黑质的小鼠的α-突触核蛋白相关病理。综上所述，这些结果强调了CLR01是一种治疗帕金森病的疾病修正疗法，并支持进一步的临床研究。CLR01是一种抑制蛋白质聚集的分子镊子。在这里，作者表明，CLR01在体外和体内保护人类神经元和小鼠模型中的多巴胺能神经元，显示出作为帕金森氏病疾病修饰疗法的潜力。
Parkinson’s disease (PD) affects millions of patients worldwide and is characterized by alpha-synuclein aggregation in dopamine neurons. Molecular tweezers have shown high potential as anti-aggregation agents targeting positively charged residues of proteins undergoing amyloidogenic processes. Here we report that the molecular tweezer CLR01 decreased aggregation and toxicity in induced pluripotent stem cell-derived dopaminergic cultures treated with PD brain protein extracts. In microfluidic devices CLR01 reduced alpha-synuclein aggregation in cell somas when axonal terminals were exposed to alpha-synuclein oligomers. We then tested CLR01 in vivo in a humanized alpha-synuclein overexpressing mouse model; mice treated at 12 months of age when motor defects are mild exhibited an improvement in motor defects and a decreased oligomeric alpha-synuclein burden. Finally, CLR01 reduced alpha-synuclein-associated pathology in mice injected with alpha-synuclein aggregates into the striatum or substantia nigra. Taken together, these results highlight CLR01 as a disease-modifying therapy for PD and support further clinical investigation. CLR01 is a molecular tweezer that inhibits protein aggregation. Here the authors show that CLR01 protects dopaminergic neurons in vitro and in vivo in human neurons and in mouse models showing potential as a disease-modifying therapy for Parkinson’s disease.
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DOI：
10.1083/jcb.85.3.890
发表时间：
1980-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
McCarthy KD;de Vellis J
通讯作者：
de Vellis J
影响因子：
23.9
作者：
Lang, Charmaine;Campbell, Kieran R.;Wade-Martins, Richard
通讯作者：
Wade-Martins, Richard
影响因子：
64.8
作者：
Kriks, Sonja;Shim, Jae-Won;Piao, Jinghua;Ganat, Yosif M.;Wakeman, Dustin R.;Xie, Zhong;Carrillo-Reid, Luis;Auyeung, Gordon;Antonacci, Chris;Buch, Amanda;Yang, Lichuan;Beal, M. Flint;Surmeier, D. James;Kordower, Jeffrey H.;Tabar, Viviane;Studer, Lorenz
通讯作者：
Studer, Lorenz
影响因子：
12.7
作者：
Bengoa-Vergniory N;Roberts RF;Wade-Martins R;Alegre-Abarrategui J
通讯作者：
Alegre-Abarrategui J
影响因子：
15.1
作者：
Frank-Cannon TC;Alto LT;McAlpine FE;Tansey MG
通讯作者：
Tansey MG