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A similar reversal of disease phenotype is also accomplished by converting astrocytes to neurons using antisense oligonucleotides to transiently suppress PTB. Notably, re-innervation of striatum is accompanied by restoration of dopamine levels and rescue of motor deficits. 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. Astrocytes from different brain regions are converted to different neuronal subtypes. Applying this approach to the mouse brain, we demonstrate progressive conversion of astrocytes to new neurons that innervate into and repopulate endogenous neural circuits. 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). 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 2. Similar to other major neurodegenerative disorders, there are no disease-modifying treatments for Parkinson's disease. disease is characterized by loss of dopamine neurons in the substantia nigra 1. 10 Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA, USA.

9 Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.

8 Department of Neurosciences and Center for Neural Circuits and Behavior, University of California, San Diego, La Jolla, CA, USA.

7 Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA, USA.

6 Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.

5 Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.

4 Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.

3 MOE Key Lab of Medical Electrophysiology, ICR, Southwest Medical University, Luzhou, China.

2 State Key Laboratory of Membrane Biology and Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, China.

1 Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.