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-α-synuclein (α-syn) to target substantia nigra dopamine neurons to produce an α-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.
Highlights
Our goal is to review adeno-associated virus (AAV) vector-based gene therapy approaches to overexpress neurotrophic proteins in the striatum or substantia nigra and discuss the use of AAVs as tools to produce Parkinson’s disease models in animals
The results of limited efficacy for the AAV-NRTN trial when injected into putamen, together with findings that four to five years after diagnosis of Parkinson’s disease there are few tyrosine hydroxylase (TH) fibres left in the putamen [48], led to clinical trials targeting the substantia nigra [31]
The results described above suggest that such overloading of substantia nigra dopamine neurons with either RNA or protein can be caused by the overexpression of WT, mutant α-syn, green fluorescent protein (GFP), untranslated RNA, or perhaps by any non-specific sequence
Summary
Our goal is to review adeno-associated virus (AAV) vector-based gene therapy approaches to overexpress neurotrophic proteins in the striatum or substantia nigra and discuss the use of AAVs as tools to produce Parkinson’s disease models in animals. AAV-GDNF has been effective in promoting functional recovery in rat models and in primate models of Parkinson’s disease [26,27] and is currently in a clinical trial coordinated by the NIH Clinical Center [28,29] Another AAV-based neurotrophic factor therapy for human Parkinson’s disease patients has been neurturin (NRTN), a protein in the same family as GDNF [30]. The trials described above bring up an important aspect of human gene therapy when targeting dopamine neurons for restoration purposes: whether to target the striatum/putamen or the substantia nigra This is especially relevant since in Parkinson’s disease the axons along the nigrostriatal tract are degenerating before the dopamine neuron bodies in the substantia nigra [41], and it is not clear how axonopathy impacts the efficacy of functional restoration after striatum/putamen administration. It is likely that the optimal location, striatum/putamen or substantia nigra, as anatomical target for AAV injection is different depending on the therapeutic protein [23]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
