Journal ArticleDOI
Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model
Pia Rivetti di Val Cervo,Roman A. Romanov,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,Tibor Harkany,Gilberto Fisone,Ernest Arenas +17 more
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TLDR
This work uses three transcription factors, NEUROD1, ASCL1 and LMX1A, and the microRNA miR218 to reprogram human and mouse astrocytes in vitro and in vivo into induced dopamine neurons (iDANs), which may enable clinical therapies for Parkinson's disease by delivery of genes rather than cells.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.read more
Citations
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Journal ArticleDOI
Parkinson's disease motor symptoms rescue by CRISPRa‐reprogramming astrocytes into GABAergic neurons
Jessica Giehrl-Schwab,Florian Giesert,Benedict Samuel Rauser,Chu Lan Lao,Sina Hembach,Sandrine Lefort,Ignacio L. Ibarra,Christina Koupourtidou,Malte D Luecken,Dong-Jiunn Jeffery Truong,Judith Fischer-Sternjak,Giacomo Masserdotti,Nilima Prakash,Jovica Ninkovic,Sabine M. Hölter,Daniela Vogt-Weisenhorn,Fabian J. Theis,Magdalena Götz,Wolfgang Wurst +18 more
TL;DR: A knock‐in mouse line carrying a dual dCas9 transactivator system allowing the conditional in vivo activation of endogenous genes and an AAV‐dCAS approach to enable an alternative route for clinical therapies of Parkinson's disease suggest a novel intervention strategy beyond the restoration of dopamine levels.
Posted ContentDOI
Transcription factor-based gene therapy to treat glioblastoma through direct neuronal conversion
TL;DR: The results suggest that GBM cells can be reprogrammed into different subtypes of neurons, leading to a potential alternative approach to treat brain tumor.
Book ChapterDOI
Stem Cell Treatments for Parkinson’s Disease
Thomas B Stoker,Thomas B Stoker +1 more
TL;DR: Stem cell-based treatments are emerging as the most promising approach for the development of a useful regenerative treatment that could be used in a large number of patients in Parkinson’s disease.
Journal ArticleDOI
Inflammatory Mechanisms in Parkinson's Disease: From Pathogenesis to Targeted Therapies.
Stellina Y H Lee,Nathanael J. Yates,Nathanael J. Yates,Susannah J. Tye,Susannah J. Tye,Susannah J. Tye +5 more
TL;DR: In this article, the authors summarize the data about main inflammatory biomarkers described in Parkinson's disease to date and their potential for regulation as a novel target for disease-modifying pharmacological strategies.
Journal ArticleDOI
Molecular mechanisms of developmental pathways in neurological disorders: a pharmacological and therapeutic review
Niraj K. Jha,Wei-Chih Chen,Sanjay Kumar,Rajnish R Dubey,Lung Wen Tsai,Rohan Kar,Saurabh Kumar Jha,P. K. Gupta,Ankur Sharma,Rohit Gundamaraju,Kumud Pant,Shalini Mani,Sandeep Singh,Ricardo B. Maccioni,T. Datta,Sachin Kumar Singh,Gaurav Gupta,Parteek Prasher,Kamal Dua,Abhijit Dey,Charu Sharma,Yasir Hayat Mughal,Janne Ruokolainen,Kavindra Kumar Kesari,Shreesh Ojha +24 more
TL;DR: This review explores the key roles of three embryonic pathways in modulating a range of homeostatic processes such as maintaining blood–brain barrier integrity, mitochondrial dynamics and neuroinflammation and extensively investigated the effect of these pathways in driving the pathophysiology of arange of disorders such as Alzheimer's, Parkinson's and diabetic neuropathy.
References
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Journal ArticleDOI
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
TL;DR: This work presents DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates, which enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression.
Journal ArticleDOI
Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.
TL;DR: Induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions is demonstrated and iPS cells, designated iPS, exhibit the morphology and growth properties of ES cells and express ES cell marker genes.
Journal ArticleDOI
Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling
Stuart M. Chambers,Christopher A. Fasano,Eirini P. Papapetrou,Mark J. Tomishima,Michel Sadelain,Lorenz Studer +5 more
TL;DR: Noggin/SB431542-based neural induction should facilitate the use of hES and hiPS cells in regenerative medicine and disease modeling and obviate the need for protocols based on stromal feeders or embryoid bodies.
Journal ArticleDOI
Direct conversion of fibroblasts to functional neurons by defined factors
Thomas Vierbuchen,Austin Ostermeier,Zhiping P. Pang,Yuko Kokubu,Thomas C. Südhof,Marius Wernig +5 more
TL;DR: In this paper, a combination of three transcription factors, Ascl1, Brn2 (also called Pou3f2) and Myt1l, was used to convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro.
Journal ArticleDOI
Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq
Amit Zeisel,Ana B. Muñoz-Manchado,Simone Codeluppi,Peter Lönnerberg,Gioele La Manno,Anna Juréus,Sueli Marques,Hermany Munguba,Liqun He,Christer Betsholtz,Christer Betsholtz,Charlotte Rolny,Gonçalo Castelo-Branco,Jens Hjerling-Leffler,Sten Linnarsson +14 more
TL;DR: Large-scale single-cell RNA sequencing is used to classify cells in the mouse somatosensory cortex and hippocampal CA1 region and found 47 molecularly distinct subclasses, comprising all known major cell types in the cortex.
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