ArticleJournal of neuroscience research2019
Downregulation of tyrosine hydroxylase phenotype after AAV injection above substantia nigra: Caution in experimental models of Parkinson's disease.
Article in Journal of neuroscience research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 31 citations in OpenAlex.
- Construct optimization for AAV-mediated human α-syn overexpression, and validation across research settings: Development of a shared tool for the research community.Journal of Parkinson's disease · 2026Article
- Protein phosphatase 2A methylation state impacts α-synucleinopathy in mouse models.Cell death discovery · 2026Article
- Effects of genetic knockdown of the serotonin transporter on established L-DOPA-induced dyskinesia and gene expression in hemiparkinsonian rats.Neuropharmacology · 2025Article
- Nonpeptidic Oxazole-Based Prolyl Oligopeptidase Ligands with Disease-Modifying Effects on α-Synuclein Mouse Models of Parkinson's Disease.Journal of medicinal chemistry · 2023Article
- Characterisation of functional deficits induced by AAV overexpression of alpha-synuclein in rats.Current research in neurobiology · 2023Article
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- A multisynaptic pathway from the ventral midbrain toward spinal motoneurons in monkeys.The Journal of physiology · 2022Article
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- Sequential or Simultaneous Injection of Preformed Fibrils and AAV Overexpression of Alpha-Synuclein Are Equipotent in Producing Relevant Pathology and Behavioral Deficits.Journal of Parkinson's disease · 2022Article
- Divergent Whole Brain Projections from the Ventral Midbrain in Macaques.Cerebral cortex (New York, N.Y. : 1991) · 2021Article
- TP53INP1 exerts neuroprotection under ageing and Parkinson's disease-related stress condition.Cell death & disease · 2021Article
- Endoplasmic Reticulum Stress Regulators: New Drug Targets for Parkinson's Disease.Journal of Parkinson's disease · 2021Review
- Comparative analyses of transgene expression patterns after intra-striatal injections of rAAV2-retro in rats and rhesus monkeys: A light and electron microscopic study.The European journal of neuroscience · 2020Article
- Astrocyte-specific deletion of the transcription factor Yin Yang 1 in murine substantia nigra mitigates manganese-induced dopaminergic neurotoxicity.The Journal of biological chemistry · 2020Article
- Classification of α-synuclein-induced changes in the AAV α-synuclein rat model of Parkinson's disease using electrophysiological measurements of visual processing.Scientific reports · 2020Article
- Impact of α-synuclein pathology on transplanted hESC-derived dopaminergic neurons in a humanized α-synuclein rat model of PD.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Cre-inducible Adeno Associated Virus-mediated Expression of P301L Mutant Tau Causes Motor Deficits and Neuronal Degeneration in the Substantia Nigra.Neuroscience · 2019Article
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
Adeno-associated virus (AAV) vector-mediated delivery of human α-synuclein (α-syn) gene in rat substantia nigra (SN) results in increased expression of α-syn protein in the SN and striatum which can progressively degenerate dopaminergic neurons. Therefore, this model is thought to recapitulate the neurodegeneration in Parkinson's disease. Here, using AAV to deliver α-syn above the SN in male and female rats resulted in clear expression of human α-syn in the SN and striatum. The protein was associated with moderate behavioral deficits and some loss of tyrosine hydroxylase (TH) in the nigrostriatal areas. However, the immunohistochemistry results were highly variable and showed little to no correlation with behavior and the amount of α-syn present. Expression of green fluorescent protein (GFP) was used as a control to monitor gene delivery and expression efficacy. AAV-GFP resulted in a similar or greater TH loss compared to AAV-α-syn and therefore an additional vector that does not express a protein was tested. Vectors with double-floxed inverse open reading frame (DIO ORF) encoding fluorescent proteins that generate RNA that is not translated also resulted in TH downregulation in the SN but showed no significant behavioral deficits. These results demonstrate that although expression of wild-type human α-syn can cause neurodegeneration, the variability and lack of correlation with outcome measures are drawbacks with the model. Furthermore, design and control selection should be considered carefully because of conflicting conclusions due to AAV downregulation of TH, and we recommend caution with having highly regulated TH as the only marker for the dopamine system.
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