AAV Vector-Mediated Gene Delivery to Substantia Nigra Dopamine Neurons : Implications for Gene Therapy and Disease Models

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Albert , K , Voutilainen , M H , Domanskyi , A & Airavaara , M 2017 , ' AAV Vector-Mediated Gene Delivery to Substantia Nigra Dopamine Neurons : Implications for Gene Therapy and Disease Models ' , Genes , vol. 8 , no. 2 , 63 . https://doi.org/10.3390/genes8020063

Title: AAV Vector-Mediated Gene Delivery to Substantia Nigra Dopamine Neurons : Implications for Gene Therapy and Disease Models
Author: Albert, Katrina; Voutilainen, Merja H.; Domanskyi, Andrii; Airavaara, Mikko
Contributor: University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
Date: 2017-02
Language: eng
Number of pages: 15
Belongs to series: Genes
ISSN: 2073-4425
URI: http://hdl.handle.net/10138/183659
Abstract: Gene delivery using adeno-associated virus (AAV) vectors is a widely used method to transduce neurons in the brain, especially due to its safety, efficacy, and long-lasting expression. In addition, by varying AAV serotype, promotor, and titer, it is possible to affect the cell specificity of expression or the expression levels of the protein of interest. Dopamine neurons in the substantia nigra projecting to the striatum, comprising the nigrostriatal pathway, are involved in movement control and degenerate in Parkinson's disease. AAV-based gene targeting to the projection area of these neurons in the striatum has been studied extensively to induce the production of neurotrophic factors for disease-modifying therapies for Parkinson's disease. Much less emphasis has been put on AAV-based gene therapy targeting dopamine neurons in substantia nigra. We will review the literature related to targeting striatum and/or substantia nigra dopamine neurons using AAVs in order to express neuroprotective and neurorestorative molecules, as well as produce animal disease models of Parkinson's disease. We discuss difficulties in targeting substantia nigra dopamine neurons and their vulnerability to stress in general. Therefore, choosing a proper control for experimental work is not trivial. Since the axons along the nigrostriatal tract are the first to degenerate in Parkinson's disease, the location to deliver the therapy must be carefully considered. We also review studies using AAV--synuclein (-syn) to target substantia nigra dopamine neurons to produce an -syn overexpression disease model in rats. Though these studies are able to produce mild dopamine system degeneration in the striatum and substantia nigra and some behavioural effects, there are studies pointing to the toxicity of AAV-carrying green fluorescent protein (GFP), which is often used as a control. Therefore, we discuss the potential difficulties in overexpressing proteins in general in the substantia nigra.
Subject: adeno-associated virus
alpha-synuclein
Parkinson's disease
substantia nigra
dopamine
neurotrophic factors
GDNF
striatum
gene therapy
GFP
ADENOASSOCIATED VIRUS VECTORS
CENTRAL-NERVOUS-SYSTEM
CONVECTION-ENHANCED DELIVERY
PARKINSONS-DISEASE
ALPHA-SYNUCLEIN
RAT MODEL
NIGROSTRIATAL SYSTEM
NEUROTROPHIC FACTOR
VIRAL VECTORS
TYROSINE-HYDROXYLASE
1184 Genetics, developmental biology, physiology
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