The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons
Open accessAbstract
Parkinson's disease (PD) is characterised by the progressive loss of nigral dopamine neurons and the presence of synucleinopathy. Overexpression of α-synuclein in vivo using viral vectors has opened interesting possibilities to model PD-like pathology in rodents. However, the attempts made so far have failed to show a consistent behavioural phenotype and pronounced dopamine neurodegeneration. Using a more efficient adeno-associated viral (AAV) vector construct, which includes a WPRE enhancer element and uses the neuron-specific synapsin-1 promoter to drive the expression of human wild-type α-synuclein, we have now been able to achieve increased levels of α-synuclein in the transduced midbrain dopamine neurons sufficient to induce profound deficits in motor function, accompanied by reduced expression of proteins involved in dopamine neurotransmission and a time-dependent loss of nigral dopamine neurons, that develop progressively over 2-4 months after vector injection. As in human PD, nigral cell loss was preceded by degenerative changes in striatal axons and terminals, and the appearance of α-synuclein positive inclusions in dystrophic axons and dendrites, supporting the idea that α-synuclein-induced pathology hits the axons and terminals first and later progresses to involve also the cell bodies. The time-course of changes seen in the AAV-α-synuclein treated animals defines distinct stages of disease progression that matches the pre-symptomatic, early symptomatic, and advanced stages seen in PD patients. This model provides new interesting possibilities for studies of stage-specific pathologic mechanisms and identification of targets for disease-modifying therapeutic interventions linked to early or late stages of the disease.
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Self-citationα-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease
Di Maio, R., Barrett, P. J., Hoffman, E. K., Barrett, C. W., Zharikov, A., Borah, A., Hu, X., McCoy, J., Chu, C. T., Burton, E. A., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf3634 · Cited by 619
Neuronal Cell Death Mechanisms in Major Neurodegenerative Diseases
Chi, H., Chang, H.-Y., & Sang, T.-K. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103082 · Cited by 412
Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons
Lundblad, M., Decressac, M., Mattsson, B., & Björklund, A. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1200575109 · Cited by 292
Self-citationMicroglial phenotypes in Parkinson’s disease and animal models of the disease
Joers, V., Tansey, M. G., Mulas, G., & Carta, A. R. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.04.006 · Cited by 285
Metadata
- Authors
- Decressac, M., Mattsson, B., Lundblad, M., Weikop, P., & Björklund, A.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 45
- Issue
- 3
- Pages
- 939-953
- ISSN
- 0969-9961 (ISSN-L)
- OpenAlex
- W2120001716
- Cited by
- 286
- References
- 44
- FWCI
- 6.77
- Type
- journal article
- Language
- en
- Open access
- green
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- Decressac, M., Mattsson, B., Lundblad, M., Weikop, P., & Björklund, A. (2012). Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons. Neurobiology of Disease. https://doi.org/10.1016/j.nbd.2011.12.013
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