Increased SOD1 association with chromatin, DNA damage, p53 activation, and apoptosis in a cellular model of SOD1-linked ALS

Barbosa, Lívea Fujita; Cerqueira, Fernanda M.; Macedo, Antero F.A.; Garcia, Camila; Angeli, José Pedro Friedmann; Schumacher, Robert I.; Sogayar, Mari Cleide; Augusto, Ohára; Carrı̀, Maria Teresa; Mascio, Paolo Di; Medeiros, Marisa H. G.

doi:10.1016/j.bbadis.2010.01.011

Cited by 60 publications

(46 citation statements)

References 52 publications

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“…The process of DNA-triggered aggregation of oxidized SOD1 proteins was proposed as follows: association of the oxidized SOD1 proteins with DNA, reduction in the positive charges that might involve the prevention of SOD1 proteins from aggregation, enhancement in hydrophobicity, concentration of oxidized SOD1 proteins along DNA, association each other of DNA-bound oxidized SOD1 molecules, finally, formation of protein aggregates by the hydrophobic interactions. Recently, increasing evidence shows that indirect and direct interactions can occur between SOD1 and DNA or RNA both inside and outside cells [65]–[69]. Therefore, understanding the nucleic acid binding property of SOD1 might be in favor of understanding the intermolecular forces driving SOD1 aggregation, and provide a plausible explanation for the SOD1-induced ALS.…”

Section: Discussionmentioning

confidence: 99%

DNA-Triggered Aggregation of Copper, Zinc Superoxide Dismutase in the Presence of Ascorbate

Yin

Jian

et al. 2010

PLoS ONE

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The oxidative damage hypothesis proposed for the function gain of copper, zinc superoxide dismutase (SOD1) maintains that both mutant and wild-type (WT) SOD1 catalyze reactions with abnormal substrates that damage cellular components critical for viability of the affected cells. However, whether the oxidative damage of SOD1 is involved in the formation of aggregates rich in SOD1 or not remains elusive. Here, we sought to explore the oxidative aggregation of WT SOD1 exposed to environments containing both ascorbate (Asc) and DNA under neutral conditions. The results showed that the WT SOD1 protein was oxidized in the presence of Asc. The oxidation results in the higher affinity of the modified protein for DNA than that of the unmodified protein. The oxidized SOD1 was observed to be more prone to aggregation than the WT SOD1, and the addition of DNA can significantly accelerate the oxidative aggregation. Moreover, a reasonable relationship can be found between the oxidation, increased hydrophobicity, and aggregation of SOD1 in the presence of DNA. The crucial step in aggregation is neutralization of the positive charges on some SOD1 surfaces by DNA binding. This study might be crucial for understanding molecular forces driving the protein aggregation.

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Section: Discussionmentioning

confidence: 99%

DNA-Triggered Aggregation of Copper, Zinc Superoxide Dismutase in the Presence of Ascorbate

Yin

Jian

et al. 2010

PLoS ONE

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“…PC12 cells overexpressing the same SOD1 mutated gene had elevated p53 expression and phosphorylation [66]. Human neuroblastoma SH-SY5Y cells expressing another SOD1 mutant, G93A, typical for familial ALS, also exhibited increased p53 activity and apoptotic rate [90]. Interestingly, resveratrol, a substance that increases expression of SIRT1 (Silent information regulator 1), an enzyme that deacetylates and in consequence reduces the activity of p53, delayed ALS onset and prolonged the lifetime of mice bearing the latter mutation.…”

Section: Involvement Of Neurodegenerative Disease-associated Proteinsmentioning

confidence: 99%

P53 Dysfunction in Neurodegenerative Diseases - The Cause or Effect of Pathological Changes?

Szybińska

Leśniak

2017

Aging and disease

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Neurodegenerative diseases are a heterogeneous, mostly age-associated group of disorders characterized by progressive neuronal loss, the most prevalent being Alzheimer disease. It is anticipated that, with continuously increasing life expectancy, these diseases will pose a serious social and health problem in the near feature. Meanwhile, however, their etiology remains largely obscure even though all possible novel clues are being thoroughly examined. In this regard, a concept has been proposed that p53, as a transcription factor controlling many vital cellular pathways including apoptosis, may contribute to neuronal death common to all neurodegenerative disorders. In this work, we review the research devoted to the possible role of p53 in the pathogenesis of these diseases. We not only describe aberrant changes in p53 level/activity observed in CNS regions affected by particular diseases but, most importantly, put special attention to the complicated reciprocal regulatory ties existing between p53 and proteins commonly regarded as pathological hallmarks of these diseases, with the ultimate goal to identify the primary element of their pathogenesis.

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“…The abnormal regulation of p53 has been observed in ALS patients [134], and cellular and animal ALS models [135,136]. Interestingly, p53 acetylation at K320 through p300/CBP and PCAF serves as a prosurvival signal, and promotes neurite outgrowth and neuronal maturation [137].…”

Section: Alsmentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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Increased SOD1 association with chromatin, DNA damage, p53 activation, and apoptosis in a cellular model of SOD1-linked ALS

Cited by 60 publications

References 52 publications

DNA-Triggered Aggregation of Copper, Zinc Superoxide Dismutase in the Presence of Ascorbate

DNA-Triggered Aggregation of Copper, Zinc Superoxide Dismutase in the Presence of Ascorbate

P53 Dysfunction in Neurodegenerative Diseases - The Cause or Effect of Pathological Changes?

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

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