Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2017-04-10

AUTHORS

Pia Rivetti di Val Cervo, Roman A Romanov, Giada Spigolon, Débora Masini, Elisa Martín-Montañez, Enrique M Toledo, Gioele La Manno, Michael Feyder, Christian Pifl, Yi-Han Ng, Sara Padrell Sánchez, Sten Linnarsson, Marius Wernig, Tibor Harkany, Gilberto Fisone, Ernest Arenas

ABSTRACT

Cell replacement therapies for neurodegenerative disease have focused on transplantation of the cell types affected by the pathological process. Here we describe an alternative strategy for Parkinson's disease in which dopamine neurons are generated by direct conversion of astrocytes. Using three transcription factors, NEUROD1, ASCL1 and LMX1A, and the microRNA miR218, collectively designated NeAL218, we reprogram human astrocytes in vitro, and mouse astrocytes in vivo, into induced dopamine neurons (iDANs). Reprogramming efficiency in vitro is improved by small molecules that promote chromatin remodeling and activate the TGFβ, Shh and Wnt signaling pathways. The reprogramming efficiency of human astrocytes reaches up to 16%, resulting in iDANs with appropriate midbrain markers and excitability. In a mouse model of Parkinson's disease, NeAL218 alone reprograms adult striatal astrocytes into iDANs that are excitable and correct some aspects of motor behavior in vivo, including gait impairments. With further optimization, this approach may enable clinical therapies for Parkinson's disease by delivery of genes rather than cells. More... »

PAGES

444-452

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nbt.3835

DOI

http://dx.doi.org/10.1038/nbt.3835

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1084752412

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28398344


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