The DOI matches its Crossref record; 71 of the 71 references it cites were found in a registry or an index.
Age-associated increases of α-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion: Is this the target for Parkinson's disease?
Open accessAbstract
α-Synuclein is a synaptic protein that has been directly linked to both the etiology and pathogenesis of Parkinson's disease. We have previously shown that only nigral neurons in PD expressing α-synuclein inclusions display a loss dopaminergic phenotype. The present study tested the hypothesis that normal aging contributes to this effect. The relative abundance of α-synuclein protein within individual nigral neurons was quantified in eighteen normal humans between the age of 18 and 102 and twenty four rhesus monkeys between the age of 2 and 34. Optical densitometry revealed a robust age-related increase in α-synuclein protein within individual nigral neurons in both species. This effect was specific for nigral α-synuclein as no age-related changes were found in the ventral tegmental area nor were there changes in the nigra for non-pathogenic β-synuclein. The age-related increases in nigral α-synuclein were non-aggregated and strongly associated with age-related decreases in tyrosine hydroxylase (TH), the rate limiting enzyme for dopamine production. In fact, only cells expressing α-synuclein displayed reductions in TH. We hypothesize that age-related increases in α-synuclein result in a subthreshold degeneration of nigrostriatal dopamine which, in PD, becomes symptomatic due to lysosomal failure resulting in protein misfolding and inclusion formation. We further hypothesize that preventing the age-related accumulation of non-aggregated α-synuclein might be a simple and potent therapeutic target for patients with PD.
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Cites
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Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease
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Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
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α-Synuclein Locus Triplication Causes Parkinson's Disease
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AGEING AND PARKINSON'S DISEASE: SUBSTANTIA NIGRA REGIONAL SELECTIVITY
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Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism
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A Drosophila model of Parkinson's disease
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Impaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy
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“…be cleared by the proteosome, it is becoming more clear that α-synuclein is selectively translocated into lysosomes for degradation by chaperone-mediated autophagy (Cuervo et al., 2004; Lee et al., 2004; Rockenstein et al., 2005), perhaps in collaboration with the proteosome (Mandel et al., 2005).”
Background
Cited by
Poewe, W., Seppi, K., Tanner, C. M., Halliday, G. M., Brundin, P., Volkmann, J., Schrag, A.-E., & Lang, A. E. (2017) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2017.13 · Cited by 5,415
Li, J.-Y., Englund, E., Holton, J. L., Soulet, D., Hagell, P., Lees, A. J., Lashley, T., Quinn, N. P., Rehncrona, S., Björklund, A., et al. (2008) · Nature Medicine · doi:10.1038/nm1746 · Cited by 1,845
Lewy body–like pathology in long-term embryonic nigral transplants in Parkinson's disease
Kordower, J. H., Chu, Y., Hauser, R. A., Freeman, T. B., & Olanow, C. W. (2008) · Nature Medicine · doi:10.1038/nm1747 · Cited by 1,722
Self-citationVolpicelli-Daley, L. A., Luk, K. C., Patel, T. P., Tanik, S. A., Riddle, D. M., Stieber, A., Meaney, D. F., Trojanowski, J. Q., & Lee, V. M.-Y. (2011) · Neuron · doi:10.1016/j.neuron.2011.08.033 · Cited by 1,569
-Synuclein in Parkinson's Disease
Stefanis, L. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a009399 · Cited by 1,446
Metadata
- Authors
- Chu, Y., & Kordower, J. H.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2007-01
- Volume
- 25
- Issue
- 1
- Pages
- 134-149
- ISSN
- 0969-9961 (ISSN-L)
- OpenAlex
- W2084334114
- Cited by
- 396
- References
- 71
- FWCI
- 12.13
- Type
- journal article
- Language
- en
- Open access
- green
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- Chu, Y., & Kordower, J. H. (2007). Age-associated increases of α-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion: Is this the target for Parkinson's disease? Neurobiology of Disease. https://doi.org/10.1016/j.nbd.2006.08.021
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
