Behavioral and Neurochemical Effects of Wild-Type and Mutated Human α-Synuclein in Transgenic Mice
Abstract
Human alpha-synuclein (halpha-SYN) is implicated in the Parkinson's disease phenotype (PDP) based on a variety of studies in man, animal models, and in vitro studies. The normal function of halpha-SYN and the mechanism by which it contributes to the PDP remains unclear. We created transgenic mice expressing either wild-type (hwalpha-SYN) or a doubly mutated (hm2alpha-SYN) form of halpha-SYN under control of the 9-kb rat tyrosine hydroxylase promoter. These mice expressed halpha-SYN in cell bodies, axons, and terminals of the nigrostriatal system. The expression of halpha-SYN in nigrostriatal terminals produced effects in both constructs resulting in increased density of the dopamine transporter and enhanced toxicity to the neurotoxin MPTP. Expression of hm2alpha-SYN reduced locomotor responses to repeated doses of amphetamine and blocked the development of sensitization. Adult hwalpha-SYN-5 transgenic mice had unremarkable dopaminergic axons and terminals, normal age-related measures on two motor coordination screens, and normal age-related measures of dopamine (DA) and its metabolites. Adult hm2alpha-SYN-39 transgenic mice had abnormal axons and terminals, age-related impairments in motor coordination, and age-related reductions in DA and its metabolites. Expression of hm2alpha-SYN adversely affects the integrity of dopaminergic terminals and leads to age-related declines in motor coordination and dopaminergic markers.
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Overexpression of wild-type or mutant human α-synuclein caused by the TH promoter did not result in formation of pathological inclusions nor alter behavior and sensitivity to MPTP in C57BL/6 mice.
“Because the overexpression of wild-type or mutant human α-synuclein caused by the TH promoter did not result in the formation of pathological inclusions nor alter the behavior and sensitivity to 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) in C57BL/6 mice [117,118,119]”
From Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia (2020) · cites this paper as [119]
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References 53 · Cited by 285
- Authors
- Richfield, E. K., Thiruchelvam, M. J., Cory-Slechta, D. A., Wuertzer, C., Gainetdinov, R. R., Caron, M. G., Di Monte, D. A., & Federoff, H. J.
- Affiliations
- University of Rochester Medicine (US)
- Howard Hughes Medical Institute (US)
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2002-05
- Volume
- 175
- Issue
- 1
- Pages
- 35-48
- ISSN
- 0014-4886 (ISSN-L)
- OpenAlex
- W1965111978
- Cited by
- 285
- References
- 53
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 11 · 2023: 3 · 2022: 11 · 2021: 9 · 2020: 9 · 2019: 3 · 2018: 7 · 2017: 7 · 2016: 5 · 2015: 5 · 2014: 13 · 2013: 13 · 2012: 16
- FWCI
- 11.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01es005905-04, 5r01es009391-05)
- National Institute of Neurological Disorders and Stroke (NS-19576, R01NS036420, R01NS019576, NS 36420)
- National Institute of Environmental Health Sciences (ES-01247, R01 ES09391, R01ES005017, ES 05905, ES 05017, P30ES001247)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Keywords
- alpha-synuclein, Parkinson's disease, transgenic mice, alpha-synuclein mutations, dopamine transporter, MPTP-induced neurotoxicity, dopaminergic terminals, nigrostriatal pathway, amphetamine sensitization, motor coordination, dopamine metabolites, age-related motor decline
- MeSH terms
- Aging, Amphetamine, Animals, Behavior, Animal, Brain, Corpus Striatum, Disease Models, Animal, Dopamine, Humans, Membrane Glycoproteins, Mice, Transgenic, Motor Activity, Nerve Tissue Proteins, Parkinson Disease, Parkinson Disease, Secondary, Promoter Regions, Genetic, Substantia Nigra, Tyrosine 3-Monooxygenase, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Mutagenesis, Site-Directed, Presynaptic Terminals, Disease Progression, Genetic Predisposition to Disease, Membrane Transport Proteins, Dopamine Plasma Membrane Transport Proteins, Mice, Synucleins, alpha-Synuclein
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