Differentiation and transcription factor gene therapy in experimental parkinson's disease: sonic hedgehog and Gli-1, but not Nurr-1, protect nigrostriatal cell bodies from 6-OHDA-induced neurodegeneration

Molecular Therapy : the Journal of the American Society of Gene Therapy
A Hurtado-LorenzoP R Löwenstein

Abstract

We tested the activity of the dopaminergic neuron differentiation factor sonic hedgehog, its downstream transcription factor target Gli-1, and an orphan nuclear receptor, Nurr-1, necessary for the induction of the dopaminergic phenotype of nigrostriatal neurons, in an in vivo model of nigrostriatal neurodegeneration. Our preliminary experiments demonstrated that all three constructs expressed the proper molecules and that these had the predicted biological activities in vitro. We expressed the N-terminal of sonic hedgehog (ShhN) and the Gli-1 and Nurr-1 entire coding regions from highly purified, and quality controlled, replication-defective adenoviral vectors injected into the brains of rats and used the dopaminergic growth factor GDNF as a positive control. The neurotoxin 6-hydroxydopamine was used to lesion the nigrostriatal dopaminergic innervation; RAd-ShhN and RAd-Gli-1 protected dopaminergic neuronal cell bodies in the substantia nigra, but not axonal terminals in the striatum, from 6-OHDA-induced cell death, while RAd-Nurr-1 was ineffective in protecting either cell bodies or axons. RAd-GDNF was able to protect both the dopaminergic cell bodies and the striatal axon terminals. Our results establish for the first time, t...Continue Reading

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Citations

Jul 18, 2014·Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·Yi ZhangHaihong Wang
Dec 6, 2005·European Journal of Nuclear Medicine and Molecular Imaging·Andreas H JacobsPedro Lowenstein
Feb 20, 2008·Molecular Therapy : the Journal of the American Society of Gene Therapy·Gwendalyn D KingMaria G Castro
Oct 8, 2011·Journal of Molecular Neuroscience : MN·Randy Peterson, John Turnbull
Sep 18, 2010·Neurochemical Research·Ruo-Lian DaiBo Hu
Feb 24, 2015·Frontiers in Cell and Developmental Biology·Vimal K SinghRamesh Chandra
May 10, 2017·Journal of Neurochemistry·Christopher I UgbodeMarcus Rattray
Aug 19, 2007·Gene Therapy·J S Greenberger
Mar 12, 2010·Journal of Neurochemistry·Elisabeth TraiffortMartial Ruat
Jun 20, 2012·The European Journal of Neuroscience·Julia FuchsRajiv L Joshi
Sep 4, 2014·Development·Ralitsa Petrova, Alexandra L Joyner

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