Age-associated increases of alpha-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion: Is this the target for Parkinson's disease?

Abstract

alpha-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 alpha-synuclein inclusions display a loss dopaminergic phenotype. The present study tested the hypothesis that normal aging contributes to this effect. The relative abundance of alpha-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 alpha-synuclein protein within individual nigral neurons in both species. This effect was specific for nigral alpha-synuclein as no age-related changes were found in the ventral tegmental area nor were there changes in the nigra for non-pathogenic beta-synuclein. The age-related increases in nigral alpha-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 alpha-synuclein displayed reductions in TH. We hypothesize that age-related increases in alpha-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 alpha-synuclein might be a simple and potent therapeutic target for patients with PD.