Reversing a model of Parkinson’s disease with in situ converted nigral neurons
Authors: Yuanchao Xue
Xinjiang Kang
Dongyang Zhang
Zhengyu Liang
Xuan Zhang
Zhuan Zhou
William C Mobley
Roy Maimon
Hao Qian
Steven F Dowdy
Don W Cleveland
Xiang-Dong Fu
Jing Hu
Neal K Devaraj
Fan Meng
Journal: Nature (2020)
Discipline: Multidisciplinary
Keywords: Parkinson's disease; dopamine neurons; neurodegenerative disorders; disease-modifying treatments; astrocytes
Affiliations: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA., State Key Laboratory of Membrane Biology and Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, China., MOE Key Lab of Medical Electrophysiology, ICR, Southwest Medical University, Luzhou, China., Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China., Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA., Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China., Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA, USA., Department of Neurosciences and Center for Neural Circuits and Behavior, University of California, San Diego, La Jolla, CA, USA., Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA. ., Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA, USA. .

Abstract:  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. 

Retracted: No

PubPeer comments:
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 Retraction, December 2021: https: www.ncbi.nlm.nih.gov labs pmc articles PMC8748120  Falsified materials and or data reported in this publication have been detected by a knowledgeable reader and subsequently confirmed by further investigation of editorial office. Therefore, the entire article has been retracted in accordance with this journalu2019s policy and editorial decision. ,