Reversing a model of Parkinson's disease with in situ converted nigral neurons.
Reversing a model of Parkinson's disease with in situ converted nigral neurons.
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DOI：
10.1038/s41586-020-2388-4
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发表时间：
2020-06
期刊：
影响因子：
64.8
通讯作者：
Fu XD
中科院分区：
文献类型：
--
作者：
Qian H;Kang X;Hu J;Zhang D;Liang Z;Meng F;Zhang X;Xue Y;Maimon R;Dowdy SF;Devaraj NK;Zhou Z;Mobley WC;Cleveland DW;Fu XD
帕金森病的特征是黑质中多巴胺神经元的丧失。与其他主要神经退行性疾病类似，不存在缓解疾病的治疗方法。虽然大多数治疗策略旨在防止神经元丢失或保护脆弱的神经元回路，但潜在的替代方案是替换丢失的神经元以重建受损的回路。在此，我们报告了通过消耗 RNA 结合蛋白 PTB，将分离的小鼠和人类星形胶质细胞有效地一步转化为功能性神经元。将这种方法应用于小鼠大脑，我们证明了星形胶质细胞逐渐转化为可以神经支配内源性神经回路的新神经元。研究发现不同大脑区域的星形胶质细胞会转化为不同的神经元亚型。使用化学诱导的帕金森病模型，我们展示了中脑星形胶质细胞转化为多巴胺能神经元，其轴突重建黑质纹状体回路。值得注意的是，纹状体的神经重新支配伴随着多巴胺水平的恢复和运动缺陷的挽救。类似的疾病表型逆转也可以通过使用反义寡核苷酸暂时抑制 PTB 将星形胶质细胞转化为神经元来实现。这些发现确定了一种潜在强大且临床可行的新方法，通过替换丢失的神经元来治疗神经退行性疾病。
Parkinson disease is characterized by loss of dopamine neurons in the substantia nigra. Similar to other major neurodegenerative disorders, no disease-modifying treatment exists. While most treatment strategies aim to prevent neuronal loss or protect vulnerable neuronal circuits, a potential alternative is to replace lost neurons to reconstruct disrupted circuits. Herein we report an efficient single-step conversion of isolated mouse and human astrocytes into functional neurons by depleting the RNA binding protein PTB. Applying this approach to the mouse brain, we demonstrate progressive conversion of astrocytes into new neurons that can innervate into endogenous neural circuits. Astrocytes in different brain regions are found to convert into different neuronal subtypes. Using a chemically induced model of Parkinson’s disease, we show conversion of midbrain astrocytes into dopaminergic neurons whose axons reconstruct the nigro-striatal circuit. Significantly, re-innervation of striatum is accompanied by restoration of dopamine levels and rescue of motor deficits. Similar disease phenotype reversal is also accomplished by converting astrocytes to neurons using antisense oligonucleotides to transiently suppress PTB. These findings identify a potentially powerful and clinically feasible new approach to treating neurodegeneration by replacing lost neurons.
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DOI：
10.1073/pnas.0700293104
发表时间：
2007-03-20
影响因子：
11.1
作者：
Armbruster, Blaine N.;Li, Xiang;Roth, Bryan L.
通讯作者：
Roth, Bryan L.
DOI：
10.1073/pnas.250471697
发表时间：
2000-12-05
影响因子：
11.1
作者：
Laywell, ED;Rakic, P;Steindler, DA
通讯作者：
Steindler, DA
影响因子：
23.9
作者：
Chen Y;Xiong M;Dong Y;Haberman A;Cao J;Liu H;Zhou W;Zhang SC
通讯作者：
Zhang SC
影响因子：
--
作者：
ABERCROMBIE, M
通讯作者：
ABERCROMBIE, M
影响因子：
3.4
作者：
Grealish, Shane;Mattsson, Bengt;Bjorklund, Anders
通讯作者：
Bjorklund, Anders