Accumulation of Misfolded Protein Through Nitrosative Stress Linked to Neurodegenerative Disorders

Uehara, Takashi

doi:10.1089/ars.2006.1517

Cited by 60 publications

(44 citation statements)

References 45 publications

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“…In brains manifesting sporadic Parkinson's or Alzheimer's disease, Snitrosylation inhibits PDI's enzymatic activity, leading to the accumulation of polyubiquitinated proteins, which activates the unfolded protein response (Uehara et al, 2006). Activation of this stress pathway, may be linked to the development of sporadic neurodegenerative diseases (Uehara, 2007). Snitrosylation of parkin also eventually leads to the accumulation of unfolded proteins and subsequent neuronal cell death ).…”

Section: No Functions In Immunity and Neurodegenerative Diseasementioning

confidence: 99%

Nitric oxide: promoter or suppressor of programmed cell death?

et al. 2010

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Nitric oxide (NO) is a short-lived gaseous free radical that predominantly functions as a messenger and effector molecule. It affects a variety of physiological processes, including programmed cell death (PCD) through cyclic guanosine monophosphate (cGMP)-dependent andindependent pathways. In this field, dominant discoveries are the diverse apoptosis networks in mammalian cells, which involve signals primarily via death receptors (extrinsic pathway) or the mitochondria (intrinsic pathway) that recruit caspases as effector molecules. In plants, PCD shares some similarities with animal cells, but NO is involved in PCD induction via interacting with pathways of phytohormones. NO has both promoting and suppressing effects on cell death, depending on a variety of factors, such as cell type, cellular redox status, and the flux and dose of local NO. In this article, we focus on how NO regulates the apoptotic signal cascade through protein S-nitrosylation and review the recent progress on mechanisms of PCD in both mammalian and plant cells.

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Section: No Functions In Immunity and Neurodegenerative Diseasementioning

confidence: 99%

Nitric oxide: promoter or suppressor of programmed cell death?

et al. 2010

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“…PDI has been shown to accumulate with neurofibrillary tangles and the dystrophic neurites of senile plaques in AD brain, and with FUS-positive ubiquitinated inclusions in human ALS patient spinal cords (107,108). Not only was there an increase in PDI expression in AD, PD, and ALS brain, the amount of S-nitrosylated PDI was also substantial (107,(109)(110)(111)(112)(113)(114)(115). S-nitrosylation of PDI, through the redox-active thiols of the a and a' domains, inhibits enzyme activity.…”

Section: The Role Of Hbcat In Protein Folding and Redox-chaperone Actmentioning

confidence: 99%

The redox switch that regulates molecular chaperones

Conway

Lee

2015

Biomolecular Concepts

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Modification of reactive cysteine residues plays an integral role in redox-regulated reactions. Oxidation of thiolate anions to sulphenic acid can result in disulphide bond formation, or overoxidation to sulphonic acid, representing reversible and irreversible endpoints of cysteine oxidation, respectively. The antioxidant systems of the cell, including the thioredoxin and glutaredoxin systems, aim to prevent these higher and irreversible oxidation states. This is important as these redox transitions have numerous roles in regulating the structure/function relationship of proteins. Proteins with redox-active switches as described for peroxiredoxin (Prx) and protein disulphide isomerase (PDI) can undergo dynamic structural rearrangement resulting in a gain of function. For Prx, transition from cysteine sulphenic acid to sulphinic acid is described as an adaptive response during increased cellular stress causing Prx to form higher molecular weight aggregates, switching its role from antioxidant to molecular chaperone. Evidence in support of PDI as a redox-regulated chaperone is also gaining impetus, where oxidation of the redox-active CXXC regions causes a structural change, exposing its hydrophobic region, facilitating polypeptide folding. In this review, we will focus on these two chaperones that are directly regulated through thiol-disulphide exchange and detail how these redox-induced switches allow for dual activity. Moreover, we will introduce a new role for a metabolic protein, the branched-chain aminotransferase, and discuss how it shares common mechanistic features with these well-documented chaperones. Together, the physiological importance of the redox regulation of these proteins under pathological conditions such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis will be discussed to illustrate the impact and importance of correct folding and chaperone-mediated activity.

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“…Several studies reported the involvement of excess generation of NO and its adducts in the etiology of multiple disease states, including insulin resistance and diabetes, atherosclerosis or Alzheimer's disease [Duplain et al, 2008;Parastatidis et al, 2007;Uehara, 2007;Yasukawa T et al, 2005;White et al, 2010].…”

Section: Nitrogen Centered Radical Species (Rns)mentioning

confidence: 99%