Glutathione Peroxidase 4 is associated with Neuromelanin in Substantia Nigra and Dystrophic Axons in Putamen of Parkinson's brain

Bellinger, Frederick P.; Bellinger, Miyoko T.; Seale, Lucia A.; Takemoto, Andrea S; Raman, Arjun V.; Miki, Takanori; Manning-Bog, Amy; Berry, Marla J.; White, Lon R.; Ross, G. Webster

doi:10.1186/1750-1326-6-8

Cited by 128 publications

(89 citation statements)

References 30 publications

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“…Glutathione peroxidase activity levels were also raised in the caudate and putamen, supporting the hypothesis that more resilient brain regions are protected from oxidative damage in Parkinson's disease (Mythri et al 2011). Another instructive study of glutathione peroxidase 4 expression within neuromelanin-containing cells in the nigra reveals an important caveat of these types of experiments (Bellinger et al 2011). In the Bellinger study, total glutathione peroxidase 4 immunoreactivity was decreased in the substantia nigra of Parkinson's victims.…”

Section: Adaptation and Sensitization To Proteotoxic Stressmentioning

confidence: 84%

Adaptation and Sensitization to Proteotoxic Stress

Leak

2013

Dose-Response

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ᮀ Although severe stress can elicit toxicity, mild stress often elicits adaptations. Here we review the literature on stress-induced adaptations versus stress sensitization in models of neurodegenerative diseases. We also describe our recent findings that chronic proteotoxic stress can elicit adaptations if the dose is low but that high-dose proteotoxic stress sensitizes cells to subsequent challenges. In these experiments, long-term, low-dose proteasome inhibition elicited protection in a superoxide dismutase-dependent manner. In contrast, acute, high-dose proteotoxic stress sensitized cells to subsequent proteotoxic challenges by eliciting catastrophic loss of glutathione. However, even in the latter model of synergistic toxicity, several defensive proteins were upregulated by severe proteotoxicity. This led us to wonder whether high-dose proteotoxic stress can elicit protection against subsequent challenges in astrocytes, a cell type well known for their resilience. In support of this new hypothesis, we found that the astrocytes that survived severe proteotoxicity became harder to kill. The adaptive mechanism was glutathione dependent. If these findings can be generalized to the human brain, similar endogenous adaptations may help explain why neurodegenerative diseases are so delayed in appearance and so slow to progress. In contrast, sensitization to severe stress may explain why defenses eventually collapse in vulnerable neurons.

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Section: Adaptation and Sensitization To Proteotoxic Stressmentioning

confidence: 84%

Adaptation and Sensitization to Proteotoxic Stress

Leak

2013

Dose-Response

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“…There is evidence suggesting that nsDAn surviving the SN degeneration may present a partial loss of their phenotypic characteristics in the PD (Kastner et al ., 1993; Miller et al ., 1999; Gonzalez-Hernandez et al ., 2001, 2004; Chu et al ., 2006), a fact that could explain why a portion of the melanin-positive SN neurons does not express TH or other dopaminergic markers in PD (Kordower et al ., 2013). DAn degeneration probably begins in the distal axon and proceeds retrogradely (dying-back process) (Galvin et al ., 1999; Cheng et al ., 2010), inducing an early inhibition of the fast axonal transport (Coleman, 2005; Morfini et al ., 2007; De Vos et al ., 2008; Neukomm & Freeman, 2014) accompanied by a decreased expression of the dopaminergic phenotype (Bellinger et al ., 2011; Cheng et al ., 2011). A similar decrease in the dopaminergic phenotype has been found in the snDAn which survive to a partial degeneration of the nigrostriatal system (which may change its DAergic phenotype by a GABAergic phenotype) (Rodriguez & Gonzalez-Hernandez, 1999; Gonzalez-Hernandez et al ., 2001), and in nigrostriatal cells of animals with a degeneration of the contralateral snDAn (Gonzalez-Hernandez et al ., 2004).…”

Section: Physiological Changes Of Dan In Pd and Agingmentioning

confidence: 99%

Parkinson's disease as a result of aging

et al. 2015

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It is generally considered that Parkinson's disease is induced by specific agents that degenerate a clearly defined population of dopaminergic neurons. Data commented in this review suggest that this assumption is not as clear as is often thought and that aging may be critical for Parkinson's disease. Neurons degenerating in Parkinson's disease also degenerate in normal aging, and the different agents involved in the etiology of this illness are also involved in aging. Senescence is a wider phenomenon affecting cells all over the body, whereas Parkinson's disease seems to be restricted to certain brain centers and cell populations. However, reviewed data suggest that Parkinson's disease may be a local expression of aging on cell populations which, by their characteristics (high number of synaptic terminals and mitochondria, unmyelinated axons, etc.), are highly vulnerable to the agents promoting aging. The development of new knowledge about Parkinson's disease could be accelerated if the research on aging and Parkinson's disease were planned together, and the perspective provided by gerontology gains relevance in this field.

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“…Oxidative stress is a contributing factor to PD, as dopamine metabolism produces hydrogen peroxide and superoxide as byproducts and also spontaneously generates highly reactive quinone molecules [150]. Studies on postmortem tissue showed that GPx4 is expressed in dopaminergic neurons of the SN in both control and PD subjects [151]. This study also found that overall GPx4 levels were significantly reduced in PD patients, but when normalized with respect to surviving cell density, GPx4 expression was higher per dopaminergic neuron in PD samples.…”

Section: Selenium Selenoproteins and Neurological Diseasementioning

confidence: 99%

Selenoproteins in Nervous System Development and Function

Pitts

Byrns

Ogawa-Wong

et al. 2014

Biol Trace Elem Res

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Selenoproteins are a distinct class of proteins that are characterized by the co-translational incorporation of selenium (Se) in the form of the 21st amino acid selenocysteine. Selenoproteins provide a key defense against oxidative stress, as many of these proteins participate in oxidation-reduction reactions neutralizing reactive oxygen species, where selenocysteine residues act as catalytic sites. Many selenoproteins are highly expressed in the brain and mouse knockout studies have determined that several are required for normal brain development. In parallel with these laboratory studies, recent reports of rare human cases with mutations in genes involved in selenoprotein biosynthesis have described individuals with an assortment of neurological problems that mirror those detailed in knockout mice. These deficits include impairments in cognition and motor function, seizures, hearing loss, and altered thyroid metabolism. Additionally, due to the fact that oxidative stress is a key feature of neurodegenerative disease, there is considerable interest in the therapeutic potential of selenium supplementation for human neurological disorders. Studies performed in cell culture and rodent models have demonstrated that selenium administration attenuates oxidative stress, prevents neurodegeneration, and counters cell signaling mechanisms known to be dysregulated in certain disease states. However, there is currently no definitive evidence in support of selenium supplementation to prevent and/or treat common neurological conditions in the general population. It appears likely, that in humans, supplementation with selenium may only benefit certain subpopulations, such as those that are either selenium-deficient or possess genetic variants that affect selenium metabolism.

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Glutathione Peroxidase 4 is associated with Neuromelanin in Substantia Nigra and Dystrophic Axons in Putamen of Parkinson's brain

Cited by 128 publications

References 30 publications

Adaptation and Sensitization to Proteotoxic Stress

Adaptation and Sensitization to Proteotoxic Stress

Parkinson's disease as a result of aging

Selenoproteins in Nervous System Development and Function

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