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Cited by 480Pluripotent Stem Cells ResearchNeurogenesis and neuroplasticity mechanismsNuclear Receptors and Signaling

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

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Qian, Hao, Kang, Xinjiang, Hu, Jing, Zhang, Dongyang, Liang, Zhengyu, Meng, Fan, Zhang, Xuan, Xue, Yuanchao +7 more·2020·Nature
DOI 10.1038/s41586-020-2388-4PMC PMC7521455
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Abstract

Parkinson's disease is characterized by loss of dopamine neurons in the substantia nigra 1. 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 circuits 2. 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.

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  • Early studies reported that suppressing PTBP1 in astrocytes or other glia could initiate neuronal transcriptional programs and produce cells resembling functional neurons in models of Parkinson's disease and retinal injury.

    “Early studies reported that suppressing PTBP1 in astrocytes or other glia could initiate neuronal transcriptional programs and produce cells resembling functional neurons in models of Parkinson’s disease and retinal injury, sparking strong enthusiasm for PTBP1 as a single-factor reprogramming node.”

    From Reverse the progression of Alzheimer’s disease through Nano-ERASER-based adult neuroregeneration (2026) · cites this paper as [15]

    The sections on astrocyte-to-neuron conversion and ASO-based rescue report that PTB suppression induced neuronal gene expression and produced functional neurons from astrocytes. The paper concerns a Parkinson’s disease model; our copy does not report conversion in a retinal-injury model, so that part of the attributed claim is unsupported. (LLM, conf=0.89)

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Cited by

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Authors
Qian, H., Kang, X., Hu, J., Zhang, D., Liang, Z., Meng, F., Zhang, X., Xue, Y., Maimon, R., Dowdy, S. F., Devaraj, N. K., Zhou, Z., Mobley, W. C., Cleveland, D. W., & Fu, X.-D.
Affiliations
  • University of California San Diego (US)
  • Peking University (CN)
  • University of Electronic Science and Technology of China (CN)
  • Chinese Academy of Sciences (CN)
Corresponding author
Fu, Xiang-Dong
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2020-06-24
Volume
582
Issue
7813
Pages
550-556
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-020-2388-4
PMC
PMC7521455
OpenAlex
W3037521146
Cited by
480
References
6
Citations by year
2026: 25 · 2025: 60 · 2024: 86 · 2023: 83 · 2022: 96 · 2021: 99 · 2020: 30
FWCI
24.98
Type
journal article
Language
en
Update notices
correction (2020-07-29)
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute of General Medical Sciences (R01GM052872, R01GM049369)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
Parkinson's disease, astrocyte-to-neuron conversion, PTBP1, substantia nigra, dopaminergic neurons, striatal reinnervation, antisense oligonucleotides, neuronal replacement, motor impairment
MeSH terms
Animals, Astrocytes, Axons, Disease Models, Animal, Dopamine, Female, Humans, Male, Neural Pathways, Parkinson Disease, Phenotype, Substantia Nigra, Neostriatum, Heterogeneous-Nuclear Ribonucleoproteins, Polypyrimidine Tract-Binding Protein, Mice, Neurogenesis, Dopaminergic Neurons, In Vitro Techniques

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