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

Neurobiol Dis. 2007 Jan;25(1):134-49. doi: 10.1016/j.nbd.2006.08.021. Epub 2006 Oct 18.


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.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Aging / metabolism*
  • Animals
  • Antiparkinson Agents / pharmacology*
  • Brain / pathology
  • Cell Count
  • Dopamine / metabolism
  • Dopamine / physiology*
  • Endopeptidase K / chemistry
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Macaca mulatta
  • Male
  • Melanins / metabolism
  • Mesencephalon / cytology
  • Mesencephalon / drug effects
  • Mesencephalon / metabolism
  • Microscopy, Confocal
  • Middle Aged
  • Neurons / drug effects
  • Neurons / metabolism
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Substantia Nigra / cytology
  • Substantia Nigra / metabolism
  • Substantia Nigra / physiology*
  • Tyrosine 3-Monooxygenase / metabolism
  • alpha-Synuclein / biosynthesis*


  • Antiparkinson Agents
  • Melanins
  • alpha-Synuclein
  • Tyrosine 3-Monooxygenase
  • Endopeptidase K
  • Dopamine