Reversing a model of Parkinson’s disease with in situ converted nigral neurons

Hao Qian, Xinjiang Kang, Jing Hu, Dongyang Zhang, Zhengyu Liang, Fan Meng, Xuan Zhang, Yuanchao Xue, Roy Maimon, Steven F. Dowdy, Neal K. Devaraj, Zhuan Zhou, William C. Mobley, Don W. Cleveland and Xiang-Dong Fu ()
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Hao Qian: University of California, San Diego
Xinjiang Kang: Peking University
Jing Hu: University of California, San Diego
Dongyang Zhang: University of California, San Diego
Zhengyu Liang: University of California, San Diego
Fan Meng: University of California, San Diego
Xuan Zhang: University of California, San Diego
Yuanchao Xue: University of California, San Diego
Roy Maimon: University of California, San Diego
Steven F. Dowdy: University of California, San Diego
Neal K. Devaraj: University of California, San Diego
Zhuan Zhou: Peking University
William C. Mobley: Department of Neurosciences and Center for Neural Circuits and Behavior, University of California, San Diego
Don W. Cleveland: University of California, San Diego
Xiang-Dong Fu: University of California, San Diego

Nature, 2020, vol. 582, issue 7813, 550-556

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2388-4

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