Conformational altered p53 affects neuronal function: relevance for the response to toxic insult and growth-associated protein 43 expression

Buizza, Laura; Prandelli, Chiara; Bonini, Sara Anna; Delbarba, Andrea; Cenini, Giovanna; Lanni, Cristina; Buoso, Erica; Racchi, Marco; Govoni, Stefano; Memo, Maurizio; Uberti, Daniela

doi:10.1038/cddis.2013.13

Cited by 31 publications

(31 citation statements)

References 59 publications

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“…p53 is crucial for the induction of genes that lead to G1 arrest following DNA damage, enabling DNA repair. AD lymphocytes express an anomalous and detectable conformational state of p53 defined as a 'mutant like' conformation [57]. p53 adopts at least two tertiary structures in vivo, known as conformations: wild-type functionally active and mutant-type functionally inactive.…”

Section: Dysregulated Cell Cycle In Lymphocytesmentioning

confidence: 99%

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

et al. 2017

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Current Alzheimer's disease (AD) diagnostics is based on cognitive testing, and detecting amyloid Aβ and τ pathology by brain imaging and assays of cerebrospinal fluid. However, biomarkers identifying complex pathways contributing to pathology are lacking, especially for early AD. Preferably, such biomarkers should be more cost-effective and present in easily available diagnostic tissues, such as blood. Here, we summarize the recent findings of potential early AD molecular diagnostic biomarkers in blood platelets, lymphocytes and erythrocytes. We review molecular alterations which refer to such main hypotheses of AD pathogenesis as amyloid cascade, oxidative and mitochondrial stress, inflammation and alterations in cell cycle regulatory molecules. The major advantage of such biomarkers is the potential ability to indicate individualized therapies in AD patients. Alzheimer's disease (AD) is the most prevalent age-related dementia worldwide and one of the major unmet, increasing medical and economic problems of the modern world. As of 2015, there were an estimated 46.8 million people with dementia worldwide. This number will increase to an estimated 74.7 million in 2030 [1].Among the neuropathological hallmarks of AD are: the progressive loss of brain neurons, synaptic degeneration and the deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) in such regions of the brain as the hippocampus, cortex and amygdala. Amyloid plaques consist mainly of 40-and 42-amino-acid Aβ peptides (Aβ40 and Aβ42). Peptides are proteolytic cleavage products of the Aβ protein precursor (APP) but with no fully elucidated biological function. NFTs are deposits of paired helical filaments composed mainly of hyperphosphorylated τ protein, a microtubule-stabilizing protein that maintains neuronal cell structure and axonal transport. Nevertheless, neither senile plaques nor NFTs are absolute hallmarks of AD dementia, because cognitively intact aged individuals may exhibit both pathological changes upon postmortem brain examination or as assessed by positron emission tomography amyloid and τ imaging agents (amyloid-PET and τ-PET) [2][3][4][5].Clinical AD manifests by aggravating dysfunction and weakening functional cognitive processes, linked to brain neuron loss that is both progressive and permanent [4], and that within several years leads to total dependence on the caregiver and eventually to death. Advances in our knowledge of AD have shown that clinical symptoms usually develop after a long preclinical pathogenic process, lasting for decades, making early AD detection in asymptomatic patients a subject of great interest [4,5]. Increasing proof demonstrates that the therapeutic methods' effectiveness is strictly contingent on the early diagnosis of AD, before the occurrence of massive neuron loss and dementia. This highlights the key importance of biochemical biomarkers for early AD diagnostics. AD diagnostics & demand for novel, improved biomarkersThe broadly accepted recommendations for AD diagnosis...

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Section: Dysregulated Cell Cycle In Lymphocytesmentioning

confidence: 99%

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

et al. 2017

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“…This antibody recognizes an epitope masked when the protein is in its native conformation and accessible only when the tertiary structure is unfolded [25,26,32,33]. Briefly, 100 µg of non-denaturated protein extracts, quantified with Bradford protein assay, or control peptide at different concentration ranging from 125 ng to 7,8 ng were coated on a plate overnight at 4°C.…”

Section: P53 Unfolded Isoform Analysismentioning

confidence: 99%

Comparison of Extracellular and Intracellular Blood Compartments Highlights Redox Alterations in Alzheimer's and Mild Cognitive Impairment Patients

Arce-Varas¹,

Abate²,

Prandelli³

et al. 2016

CAR

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Abstract:Background: Many studies suggest oxidative stress as an early feature of Alzheimer's Disease (AD). However, evidence of established oxidative stress in AD peripheral cells is still inconclusive, possibly due to both, differences in the type of samples and the heterogeneity of oxidative markers used in different studies.Objective: The aim of this study was to evaluate blood-based redox alterations in Alzheimer's Disease in order to identify a peculiar disease profile. Method:To that purpose, we measured the activity of Superoxide Dismutase, Catalase and Glutathione Peroxidase both in the extracellular and the intracellular blood compartments of AD, MCI and control subjects. The amount of an open isoform of p53 protein (unfolded p53), resulting from oxidative modifications was also determined.Results: Decreased SOD, increased GPx activity and higher p53 open isoform were found in both AD and MCI plasma compared to controls. In blood peripheral mononuclear cells, SOD activity was also decreased in both AD and MCI, and unfolded p53 increased exquisitely in younger AD males compared to controls. Conclusion:Overall, these data highlight the importance of considering both extracellular and intracellular compartments, in the determination of antioxidant enzyme activities as well as specific oxidation end-products, in order to identify peculiar blood-based redox alterations in AD pathology.

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“…101 It showed that the formation of HNEp53 adducts did not affect the native conformation of p53, unlike nitration. The nitrated and so unfolded p53 directly decreases its pro-apoptotic activity and favors the survival of damaged neurons.…”

Section: Hne: a Serial Killermentioning

confidence: 99%

Cell death and diseases related to oxidative stress:4-hydroxynonenal (HNE) in the balance

et al. 2013

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During the last three decades, 4-hydroxy-2-nonenal (HNE), a major a,b-unsaturated aldehyde product of n-6 fatty acid oxidation, has been shown to be involved in a great number of pathologies such as metabolic diseases, neurodegenerative diseases and cancers. These multiple pathologies can be explained by the fact that HNE is a potent modulator of numerous cell processes such as oxidative stress signaling, cell proliferation, transformation or cell death. The main objective of this review is to focus on the different aspects of HNE-induced cell death, with a particular emphasis on apoptosis. HNE is a special apoptotic inducer because of its abilities to form protein adducts and to propagate oxidative stress. It can stimulate intrinsic and extrinsic apoptotic pathways and interact with typical actors such as tumor protein 53, JNK, Fas or mitochondrial regulators. At the same time, due to its oxidant status, it can also induce some cellular defense mechanisms against oxidative stress, thus being involved in its own detoxification. These processes in turn limit the apoptotic potential of HNE. These dualities can imbalance cell fate, either toward cell death or toward survival, depending on the cell type, the metabolic state and the ability to detoxify.

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Conformational altered p53 affects neuronal function: relevance for the response to toxic insult and growth-associated protein 43 expression

Cited by 31 publications

References 59 publications

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

Comparison of Extracellular and Intracellular Blood Compartments Highlights Redox Alterations in Alzheimer's and Mild Cognitive Impairment Patients

Cell death and diseases related to oxidative stress:4-hydroxynonenal (HNE) in the balance

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