NADPH oxidase 2 activity in Parkinson's disease

Keeney, Matthew T.; Hoffman, Edward L.; Farmer, Kyle; Bodle, Christopher; Fazzari, Marco; Zharikov, Alevtina; Castro, Sandra L.; Hu, Xiaoping; Mortimer, Amanda; Kofler, Julia; Cifuentes-Pagano, Eugenia; Pagano, Patrick J.; Burton, Edward A.; Hastings, Teresa G.; Greenamyre, J Timothy; Maio, Roberto Di

doi:10.1016/j.nbd.2022.105754

Cited by 26 publications

(44 citation statements)

References 51 publications

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“…A modification of the PLA method was used to determine if α-synuclein undergoes increased oxidative modification in the hSyn/EAAT3 −/− neurons. In this method, 4-hydroxynonenal-α-synuclein conjugates were detected using an antibodies to these two epitopes [ 33 ]. The studies revealed a greater 4-hydroxynonenal-α-synuclein PLA signal in hSyn/EAAT3 −/− than in hSyn brain sections ( Figure S2 ).…”

Section: Resultsmentioning

confidence: 99%

“…In a separate study, the PLA method was used to identify α-synuclein—4-hydroxynonenal conjugates. For these studies the sections were incubated with mouse antibody to α-synuclein and rabbit antibody to 4-hydroxynonenal, as previously described [ 33 ]. After washing, the sections were incubated with anti-rabbit plus sense and anti-mouse minus sense oligonucleotide probes.…”

Section: Methodsmentioning

confidence: 99%

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Neuronal Oxidative Stress Promotes α-Synuclein Aggregation In Vivo

et al. 2022

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Both genetic and environmental factors increase risk for Parkinson’s disease. Many of the known genetic factors influence α-synuclein aggregation or degradation, whereas most of the identified environmental factors produce oxidative stress. Studies using in vitro approaches have identified mechanisms by which oxidative stress can accelerate the formation of α-synuclein aggregates, but there is a paucity of evidence supporting the importance of these processes over extended time periods in brain. To assess this issue, we evaluated α-synuclein aggregates in brains of three transgenic mouse strains: hSyn mice, which overexpress human α-synuclein in neurons and spontaneously develop α-synuclein aggregates; EAAT3−/− mice, which exhibit a neuron-specific impairment in cysteine uptake and resultant neuron-selective chronic oxidative stress; and double-transgenic hSyn/EAAT3−/− mice. Aggregate formation was evaluated by quantitative immunohistochemistry for phosphoserine 129 α-synuclein and by an α-synuclein proximity ligation assay. Both methods showed that the double transgenic hSyn/EAAT3−/− mice exhibited a significantly higher α-synuclein aggregate density than littermate hSyn mice in each brain region examined. Negligible aggregate formation was observed in the EAAT3−/− mouse strain, suggesting a synergistic rather than additive interaction between the two genotypes. A similar pattern of results was observed in assessments of motor function: the pole test and rotarod test. Together, these observations indicate that chronic, low-grade neuronal oxidative stress promotes α-synuclein aggregate formation in vivo. This process may contribute to the mechanism by which environmentally induced oxidative stress contributes to α-synuclein pathology in idiopathic Parkinson’s disease.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Neuronal Oxidative Stress Promotes α-Synuclein Aggregation In Vivo

et al. 2022

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“…The neuroprotective signaling actions of 10-NO2-OA were assessed using an established sub-acute rotenone model of PD in rat (15,16). First, we performed a 10-NO2-OA dose-dependent pilot study (cohort 1) treating six groups of male aged (8-9 months) Lewis rats (Envigo) for 5 days with: (i) Vehicle (Mygliol 812) (p.o.)…”

Section: Animal Study and Brain Collectionmentioning

confidence: 99%

“…Proximity ligation assay (PLA) (DUO92004-100RXN; DUO92002-100RXN; DUO92007-100RXN, Sigma-Aldrich) was performed in 4% PFA-fixed tissue or cells as previously described (15,16,18,43). Samples were incubated with specific primary antibodies to the proteins to be detected.…”

Section: Proximity Ligation Assaysmentioning

confidence: 99%

“…Our recent data reveals additional novel PD-related pathogenic events and potential therapeutic targets. These findings revealed (i) enhanced activation of the most abundant NOX isoform in brain, NADPH oxidase isoform 2 (NOX2) increased the generation of ROS and lipid peroxidation products (15), (ii) aberrant leucine-rich repeat kinase 2 (LRRK2) kinase activity that correlated with endo-lysosomal impairment (16,17), and αsynuclein-mediated impairment of mitochondrial protein import with resultant mitochondrial dysfunction (18).…”

Section: Introductionmentioning

confidence: 99%

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Neuroprotective actions of a fatty acid nitroalkene in Parkinson’s disease.

Fazzari

Maio

Keeney

et al. 2022

Preprint

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To date there are no therapeutic strategies that limit the progression of Parkinson’s disease (PD). The mechanisms underlying PD-related nigrostriatal neurodegeneration remain incompletely understood, with multiple factors modulating the course of PD pathogenesis. This includes Nrf2-dependent gene expression, oxidative stress, α-synuclein pathology, mitochondrial dysfunction, and neuroinflammation. In vitro and sub-acute in vivo rotenone rat models of PD were used to evaluate the neuroprotective potential of a clinically-safe, multi-target metabolic and inflammatory modulator, the electrophilic fatty acid nitroalkene 10-nitro-oleic acid (10-NO2-OA). In N27A dopaminergic cells and in the substantia nigra pars compacta of rats, 10-NO2-OA activated Nrf2-regulated gene expression and inhibited NOX2 and LRRK2 hyperactivation, oxidative stress, microglial activation, α-synuclein modification and downstream mitochondrial import impairment. These data reveal broad neuroprotective actions of 10-NO2-OA in a sub-acute model of PD and motivate more chronic studies in rodents and primates.

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