Protein Nitration in Parkinsonʼs Disease

Abstract

Oxidative stress has been proposed as a pathogenetic mechanism in Parkinson's disease (PD). One mechanism of oxidative cellular injury is the nitration of protein tyrosine residues, mediated by peroxynitrite, a reaction product of nitric oxide and superoxide radicals. We demonstrate here the presence of nitrotyrosine immunoreactivity in Lewy bodies within melanized neurons and in amorphous deposits associated with intact and degenerating neurons. The core of the Lewy body was frequently intensely immunolabeled, while the rim was lightly labeled or unlabeled. This likely reflects the fact that tyrosine residues of neurofilament proteins are primarily localized to Lewy body cores, and suggests that nitrotyrosine is present in neurofilament protein itself. Although these observations are as yet unable to provide a definitive link between oxidative stress and neuronal dysfunction, they demonstrate that oxidative stress has occurred within the vulnerable neurons of PD, leaving a permanent marker of oxidative modification of neuronal proteins within the target cells of neurodegeneration. In addition, these observations provide a potential link between excitotoxicity and oxidative stress within the vulnerable neurons of PD and represent a pathogenetic mechanism in common with the 2 other major age-related neurodegenerative diseases, Alzheimer disease and amyotrophic lateral sclerosis.

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…Oxidative and nitrative posttranslational modifications have been identified on proteins that may affect the disease progression [81]. This includes increased levels of oxidized protein carbonyls in the SN of PD patients [89,90] and nitration of tyrosine residues within LBs in the PD brain [91,92].…”

Oxidative stress and dopamine depletion in an intrastriatal 6-hydroxydopamine model of Parkinson’s disease

“…Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Yoritaka et al, 1996), protein carbonyls (Alam et al, 1997a,Floor and Wetzel, 1998), 8-hydroxy-2-deoxyguanosine and 8-hydroxyguanine (Alam et al, 1997b,Zhang et al, 1999, and 3-nitrotyrosine (Good et al, 1998,Giasson et al, 2000. …”

“…of the oxidative stress products 4-hydroxynonenal (HNE) (Yoritaka et al, 1996), protein carbonyls (Alam et al, 1997a,Floor andWetzel, 1998), 8-hydroxy-2-deoxyguanosine and 8-hydroxyguanine (Alam et al, 1997b,Zhang et al, 1999, and 3-nitrotyrosine (Good et al, 1998,Giasson et al, 2000.…”

Reprint of: Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…Oxidative and nitrative posttranslational modifications have been identified on proteins that may affect the disease progression [81]. This includes increased levels of oxidized protein carbonyls in the SN of PD patients [89,90] and nitration of tyrosine residues within LBs in the PD brain [91,92]. Increased 3-nitrotyrosine levels have also been detected after systemic administration of the PD-inducing toxin MPTP in baboons [93] and mice [94].…”