Alpha-synuclein expression in the substantia nigra of MPTP-lesioned non-human primates.
Changes in the expression of alpha-synuclein are likely to underlie its normal function as well as its role in pathological processes. The relationship between toxic injury and alpha-synuclein expression was assessed in the substantia nigra of squirrel monkeys treated with a single injection of MPTP and sacrificed 1 week or 1 month later. At 1 week, when stereological cell counting revealed only a small decrease (-10%) in the number of dopaminergic neurons, alpha-synuclein mRNA and protein were markedly enhanced. Increased alpha-synuclein immunoreactivity was evident at the level of neuronal fibers whereas nigral cell bodies were devoid of detectable protein. At 1 month post-MPTP, neuronal loss rose to 40%. Both alpha-synuclein mRNA and protein remained elevated but, noticeably, a robust alpha-synuclein immunoreactivity characterized a significant number of cell bodies. Neuromelanin granules are hallmarks of dopaminergic neurons in primates. Therefore, the number of alpha-synuclein-positive cells that also contained neuromelanin was counted throughout the substantia nigra. At 1 month, the vast majority of alpha-synuclein-immunoreactive neurons contained neuromelanin, and approximately 80% of the dopaminergic cell bodies that survived MPTP toxicity stained positive for alpha-synuclein. The results indicate that a single toxic insult is capable of inducing a sustained alpha-synuclein up-regulation in the primate brain. They support a direct relationship between neuronal injury and enhanced alpha-synuclein expression, and suggest that protein elevation within cell bodies may be a late feature of neurons that have endured a toxic stress.
Purisai
Maya G
MG
The Parkinson's Institute, 1170 Morse Avenue, Sunnyvale, California 94089, USA.
McCormack
Alison L
AL
Langston
William J
WJ
Johnston
Louisa C
LC
Di Monte
Donato A
DA
D000818:Animals; D002452:Cell Count; D016923:Cell Death / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D008543:Melanins / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D012453:Saimiri; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015854:Up-Regulation / Q000502:physiology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D008543:Melanins; D012333:RNA, Messenger; D051844:alpha-Synuclein; C014121:neuromelanin; D004298:Dopamine