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GDNF fails to exert neuroprotection in a rat -synuclein model of Parkinson's disease
Abstract
The neuroprotective effect of the glial cell line-derived neurotrophic factor has been extensively studied in various toxic models of Parkinson's disease. However, it remains unclear whether this neurotrophic factor can protect against the toxicity induced by the aggregation-prone protein α-synuclein. Targeted overexpression of human wild-type α-synuclein in the nigrostriatal system, using adeno-associated viral vectors, causes a progressive degeneration of the nigral dopamine neurons and the development of axonal pathology in the striatum. In the present study, we investigated, using different paradigms of delivery, whether glial cell line-derived neurotrophic factor can protect against the neurodegenerative changes and the cellular stress induced by α-synuclein. We found that viral vector-mediated delivery of glial cell line-derived neurotrophic factor into substantia nigra and/or striatum, administered 2-3 weeks before α-synuclein, was inefficient in preventing the wild-type α-synuclein-induced loss of dopamine neurons and terminals. In addition, glial cell line-derived neurotrophic factor overexpression did not ameliorate the behavioural deficit in this rat model of Parkinson's disease. Quantification of striatal α-synuclein-positive aggregates revealed that glial cell line-derived neurotrophic factor had no effect on α-synuclein aggregation. These data provide the evidence for the lack of neuroprotective effect of glial cell line-derived neurotrophic factor against the toxicity of human wild-type α-synuclein in an in vivo model of Parkinson's disease. The difference in neuroprotective efficacy of glial cell line-derived neurotrophic factor seen in our model and the commonly used neurotoxin models of Parkinson's disease, raises important issues pertinent to the interpretation of the results obtained in preclinical models of Parkinson's disease, and their relevance for the therapeutic use glial cell line-derived neurotrophic factor in patients with Parkinson's disease.
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Spillantini, M. G., Schmidt, M. L., Lee, V. M.-Y., Trojanowski, J. Q., Jakes, R., & Goedert, M. (1997) · Nature · doi:10.1038/42166 · Cited by 8,382
Direct brain infusion of glial cell line–derived neurotrophic factor in Parkinson disease
Gill, S. S., Patel, N. K., Hotton, G. R., O'Sullivan, K., McCarter, R., Bunnage, M., Brooks, D. J., Svendsen, C. N., & Heywood, P. (2003) · Nature Medicine · doi:10.1038/nm850 · Cited by 1,290
Cited by
GDNF, NGF and BDNF as Therapeutic Options for Neurodegeneration
Allen, S. J., Watson, J. J., Shoemark, D. K., Barua, N. U., & Patel, N. K. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.01.004 · Cited by 820
Whone, A., Luz, M., Boca, M., Woolley, M., Mooney, L., Dharia, S., Broadfoot, J., Cronin, D., Schroers, C., Barua, N. U., et al. (2019) · Brain · doi:10.1093/brain/awz023 · Cited by 282
Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo
Angot, E., Steiner, J. A., Lema Tomé, C. M., Ekström, P., Mattsson, B., Björklund, A., & Brundin, P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039465 · Cited by 270
Self-citationOutside in: Unraveling the Role of Neuroinflammation in the Progression of Parkinson's Disease
Troncoso-Escudero, P., Parra, A., Nassif, M., & Vidal, R. L. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00860 · Cited by 191
Mead, B. P., Kim, N., Miller, G. W., Hodges, D., Mastorakos, P., Klibanov, A. L., Mandell, J. W., Hirsh, J., Suk, J. S., Hanes, J., et al. (2017) · Nano Letters · doi:10.1021/acs.nanolett.7b00616 · Cited by 151
Metadata
- Authors
- Decressac, M., Ulusoy, A., Mattsson, B., Georgievska, B., Romero-Ramos, M., Kirik, D., & Bjorklund, A.
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-06-28
- Volume
- 134
- Issue
- 8
- Pages
- 2302-2311
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2159329523
- Cited by
- 178
- References
- 2
- FWCI
- 9.88
- Type
- journal article
- Language
- en
- Open access
- closed
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- Decressac, M., Ulusoy, A., Mattsson, B., Georgievska, B., Romero-Ramos, M., Kirik, D., & Bjorklund, A. (2011). GDNF fails to exert neuroprotection in a rat -synuclein model of Parkinson's disease. Brain. https://doi.org/10.1093/brain/awr149
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