Age-associated increases of alpha-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion: Is this the target for Parkinson's disease?
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.
Chu
Yaping
Y
Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, Chicago, IL 60612, USA.
Kordower
Jeffrey H
JH
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001921:Brain / Q000473:pathology; D002452:Cell Count; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D019286:Endopeptidase K / Q000737:chemistry; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008253:Macaca mulatta; D008297:Male; D008543:Melanins / Q000378:metabolism; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018613:Microscopy, Confocal; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000096:biosynthesis*
D000978:Antiparkinson Agents; D008543:Melanins; D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase; D019286:Endopeptidase K; D004298:Dopamine