Neuronal expression of the transcription factor gli1 using the tα1 α-tubulin promoter is neuroprotective in an experimental model of parkinson's disease

ABSTRACT Nigrostriatal neurons degenerate during Parkinson's disease. Experimentally, neurotoxins such as 6-hydroxydopamine (6-OHDA) in rodents, and MPTP in mice and non-human primates,

are used to model the disease-induced degeneration of midbrain dopaminergic neurons. Glial-cell-derived neurotrophic factor (GDNF) is a very powerful neuroprotector of dopaminergic neurons

in all species examined. However, recent reports have indicated the possibility that GDNF may, in the long term and if expressed in an unregulated manner, exert untoward effects on midbrain

dopaminergic neuronal structure and function. Although GDNF remains a powerful neurotrophin, the search for alternative therapies based on alternative and complementary mechanisms of action

to GDNF is warranted. Recently, recombinant adenovirus-derived vectors encoding the differentiation factor Sonic Hedgehog (Shh) and its downstream transcriptional activator (Gli1) were shown

to protect dopaminergic neurons in the substantia nigra pars compacta from 6-OHDA-induced neurotoxicity in rats _in vivo_. A pancellular human CMV (hCMV) promoter was used to drive the

expression of both Shh and Gli1. Since Gli1 is a transcription factor and therefore exerts its actions intracellularly, we decided to test whether expression of Gli1 within neurons would be

effective for neuroprotection. We demonstrate that neuronal-specific expression of Gli1 using the neuron-specific Tα1 α-tubulin (Tα1) promoter was neuroprotective, and its efficiency was

comparable to the pancellular strong viral hCMV promoter. These results suggest that expression of the transcription factor Gli1 solely within neurons is neuroprotective for dopaminergic

neurons _in vivo_ and, furthermore, that neuronal-specific promoters are effective within the context of adenovirus-mediated gene therapy-induced neuroprotection of dopaminergic midbrain

neurons. Since cell-type specific promoters are known to be weaker than the viral hCMV promoter, our data demonstrate that neuronal-specific expression of transcription factors is an

effective, specific, and sufficient targeted approach for neurological gene therapy applications, potentially minimizing side effects due to unrestricted promiscuous gene expression within

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Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS DELIVERY OF CDNF BY AAV-MEDIATED GENE TRANSFER PROTECTS DOPAMINE NEURONS AND REGULATES ER STRESS AND INFLAMMATION IN AN ACUTE

MPTP MOUSE MODEL OF PARKINSON’S DISEASE Article Open access 17 July 2024 CRISPR/SGRNA-DIRECTED SYNERGISTIC ACTIVATION MEDIATOR (SAM) AS A THERAPEUTIC TOOL FOR PARKINSON´S DISEASE Article

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1988. Google Scholar  Download references ACKNOWLEDGEMENTS This work in the GTRI is funded by NIH Grants 1 RO1 NS44556 (MGC), 1 RO1 NS42893 (PRL), U54 4 NS04-5309 (PRL), R21 NS47298 (PRL),

and the Kane Fellowship in Gene Therapy for Cancer Research. Dr D Suwelack was supported during part of the work described herein by a doctoral fellowship from The Wellcome Trust, UK. Drs

Andres Hurtado-Lorenzo and Enrique Millan, during their PhD work, were generously supported by predoctoral fellowships from the UK Academic Council for Foreign Graduates, the University of

Manchester, England, and the National Research Council of Venezuela. We thank Freda Miller for providing the plasmid containing the Tα1 promoter. PRL is a holder of the Bram and Elaine

Goldsmith Chair in Gene Therapeutics. We are very greateful to the Board of Governors at Cedars-Sinai Medical Center for their vision and very generous creation and support of the GTRI. We

also thank Dr Shlomo Melmed for his support and academic leadership, Mr Richard Katzman for his excellent administrative support, and Mr Nelson Jovel for the skillful editing and preparation

of the figures and manuscript for publication. AUTHOR INFORMATION Author notes * D Suwelack Present address: Neurology Clinic, Alfried Krupp Hospital, Alfried Krupp St. 21, D-45131, Essen,

Germany AUTHORS AND AFFILIATIONS * Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA D Suwelack, A Hurtado-Lorenzo, E Millan, V Gonzalez-Nicolini, K

Wawrowsky, PR Lowenstein & MG Castro * Department of Medicine, Molecular Medicine and Gene Therapy Unit, University of Manchester, Manchester, UK D Suwelack, PR Lowenstein & MG

Castro * Department of Medicine and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA PR

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PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Suwelack, D., Hurtado-Lorenzo, A., Millan, E. _et al._ Neuronal expression of the transcription factor Gli1 using

the Tα1 α-tubulin promoter is neuroprotective in an experimental model of Parkinson's disease. _Gene Ther_ 11, 1742–1752 (2004). https://doi.org/10.1038/sj.gt.3302377 Download citation

* Received: 11 June 2004 * Accepted: 16 July 2004 * Published: 01 December 2004 * Issue Date: 01 December 2004 * DOI: https://doi.org/10.1038/sj.gt.3302377 SHARE THIS ARTICLE Anyone you

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Springer Nature SharedIt content-sharing initiative KEYWORDS * adenoviral vectors * GDNF * neurodegeneration * neuron-specific promoter * dopamine * substantia nigra