Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons
Open accessAbstract
We used in vivo amperometry to monitor changes in synaptic dopamine (DA) release in the striatum induced by overexpression of human wild-type α-synuclein in nigral DA neurons, induced by injection of an adeno-associated virus type 6 (AAV6)–α-synuclein vector unilaterally into the substantia nigra in adult rats. Impairments in DA release evolved in parallel with the development of degenerative changes in the nigrostriatal axons and terminals. The earliest change, seen 10 d after vector injection, was a marked, ≈50%, reduction in DA reuptake, consistent with an early dysfunction of the DA transporter that developed before any overt signs of axonal damage. At 3 wk, when the first signs of axonal damage were observed, the amount of DA released after a KCl pulse was reduced by 70–80%, and peak DA concentration was delayed, indicating an impaired release mechanism. At later time points, 8–16 wk, overall striatal innervation density was reduced by 60–80% and accompanied by abundant signs of axonal damage in the form of α-synuclein aggregates, axonal swellings, and dystrophic axonal profiles. At this stage DA release and reuptake were profoundly reduced, by 80–90%. The early changes in synaptic DA release induced by overexpression of human α-synuclein support the idea that early predegenerative changes in the handling of DA may initiate, and drive, a progressive degenerative process that hits the axons and terminals first. Synaptic dysfunction and axonopathy would thus be the hallmark of presymptomatic and early-stage Parkinson disease, followed by neuronal degeneration and cell loss, characteristic of more advanced stages of the disease.
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Overexpression of αSyn via viral injection into the substantia nigra of mature rats reduces dopamine release and reuptake by 80-90%.
“overexpression of αSyn via viral injection into the substantia nigra of mature animals reduced dopamine release and reuptake by 80-90% [159]”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [159]
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- Authors
- Lundblad, M., Decressac, M., Mattsson, B., & Björklund, A.
- Affiliations
- Lund University (SE)
- Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, Lund 221 84, Sweden
- ORCID
- Björklund, Anders
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-02-06
- Volume
- 109
- Issue
- 9
- Pages
- 3213-3219
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3295273
- OpenAlex
- W1972715091
- Cited by
- 292
- References
- 33
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 15 · 2023: 15 · 2022: 16 · 2021: 27 · 2020: 16 · 2019: 19 · 2018: 23 · 2017: 31 · 2016: 13 · 2015: 20 · 2014: 27 · 2013: 31 · 2012: 15
- FWCI
- 19.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- alpha-synuclein, Parkinson's disease, dopamine release, dopamine transporter, nigrostriatal pathway, substantia nigra, striatum, axonal degeneration, axonopathy, synaptic dysfunction, alpha-synuclein aggregates, gene overexpression
- MeSH terms
- Dependovirus, Animals, Axons, Caudate Nucleus, Dopamine, Dose-Response Relationship, Drug, Electrodes, Implanted, Female, Genetic Vectors, Humans, Microinjections, Synaptic Transmission, Nomifensine, Potassium, Putamen, Recombinant Fusion Proteins, Substantia Nigra, Up-Regulation, Rats, Sprague-Dawley, Dopamine Uptake Inhibitors, Transgenes, Rats, alpha-Synuclein, Dopaminergic Neurons
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