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

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.

journal_name

Nature

journal_title

Nature

authors

Qian H,Kang X,Hu J,Zhang D,Liang Z,Meng F,Zhang X,Xue Y,Maimon R,Dowdy SF,Devaraj NK,Zhou Z,Mobley WC,Cleveland DW,Fu XD

doi

10.1038/s41586-020-2388-4

subject

Has Abstract

pub_date

2020-06-01 00:00:00

pages

550-556

issue

7813

eissn

0028-0836

issn

1476-4687

pii

10.1038/s41586-020-2388-4

journal_volume

582

pub_type

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