机构：[1]Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.[2]State Key Laboratory of Membrane Biology and Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, China.[3]MOE Key Lab of Medical Electrophysiology, ICR, Southwest Medical University, Luzhou, China.[4]Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.[5]Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA, USA.[6]Department of Neurosciences and Center for Neural Circuits and Behavior, University of California, San Diego, La Jolla, CA, USA.[7]Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA, USA.[8]Present address: Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China.四川省人民医院[9]Present address: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Parkinson's disease is characterized by loss of dopamine neurons in the substantia nigra1. Similar to other major neurodegenerative disorders, there are no disease-modifying treatments for Parkinson's disease. 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 circuits2. Here we report an efficient one-step conversion of isolated mouse and human astrocytes to functional neurons by depleting the RNA-binding protein PTB (also known as PTBP1). Applying this approach to the mouse brain, we demonstrate progressive conversion of astrocytes to new neurons that innervate into and repopulate endogenous neural circuits. Astrocytes from different brain regions are converted to different neuronal subtypes. Using a chemically induced model of Parkinson's disease in mouse, we show conversion of midbrain astrocytes to dopaminergic neurons, which provide axons to reconstruct the nigrostriatal circuit. Notably, re-innervation of striatum is accompanied by restoration of dopamine levels and rescue of motor deficits. A similar reversal of disease phenotype is also accomplished by converting astrocytes to neurons using antisense oligonucleotides to transiently suppress PTB. These findings identify a potentially powerful and clinically feasible approach to treating neurodegeneration by replacing lost neurons.
基金：
D.W.C. received a
salary from the Ludwig Institute for Cancer Research and is a Nomis Foundation
Distinguished Scientist. Z.Z. and X.K. were supported by NSFC grants (31930061,
31761133016, 21790394 and 81974203). W.C.M. and X.-D.F. were supported by a grant from
the Larry Hillblom Foundation (2019-A-006-NET). This work was supported by NIH grants
(GM049369 and GM052872) to X.-D.F.
第一作者机构：[1]Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
通讯作者：
通讯机构：[1]Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.[7]Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA, USA.
推荐引用方式(GB/T 7714)：
Hao Qian,Xinjiang Kang,Jing Hu,et al.Reversing a model of Parkinson's disease with in situ converted nigral neurons.[J].NATURE.2020,582(7813):550-+.doi:10.1038/s41586-020-2388-4.
APA：
Hao Qian,Xinjiang Kang,Jing Hu,Dongyang Zhang,Zhengyu Liang...&Xiang-Dong Fu.(2020).Reversing a model of Parkinson's disease with in situ converted nigral neurons..NATURE,582,(7813)
MLA：
Hao Qian,et al."Reversing a model of Parkinson's disease with in situ converted nigral neurons.".NATURE 582..7813(2020):550-+
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