Abstract
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.
Original language | English (US) |
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Pages (from-to) | 134-149 |
Number of pages | 16 |
Journal | Neurobiology of Disease |
Volume | 25 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2007 |
Externally published | Yes |
Keywords
- Aging
- Dopaminergic neuron
- Substantia nigra
- Synuclein
- Synucleinopathy
- Tyrosine hydroxylase
ASJC Scopus subject areas
- Neurology