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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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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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