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

ABSTRACT: The role of p53 in neurodegenerative diseases is essentially associated with neuronal death. Recently an alternative point of view is emerging, as altered p53 conformation and impaired protein function have been found in fibroblasts and blood cells derived from Alzheimer's disease patients. Here, using stable transfected SH-SY5Y cells overexpressing APP751wt (SY5Y-APP) we demonstrated that the expression of an unfolded p53 conformation compromised neuronal functionality. In particular, these cells showed (i) augmented expression of amyloid precursor protein (APP) and its metabolites, including the C-terminal fragments C99 and C83 and ?-amyloid peptide (ii) high levels of oxidative markers, such as 4-hydroxy-2-nonenal Michael-adducts and 3-nitro-tyrosine and (iii) altered p53 conformation, mainly due to nitration of its tyrosine residues. The consequences of high-unfolded p53 expression resulted in loss of p53 pro-apoptotic activity, and reduction of growth-associated protein 43 (GAP-43) mRNA and protein levels. The role of unfolded p53 in cell death resistance and lack of GAP-43 transcription was demonstrated by ZnCl(2) treatment. Zinc supplementation reverted p53 wild-type tertiary structure, increased cells sensitivity to acute cytotoxic injury and GAP-43 levels in SY5Y-APP clone.

SUBMITTER: Buizza L

PROVIDER: S-EPMC3734841 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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

Buizza L L Prandelli C C Bonini S A SA Delbarba A A Cenini G G Lanni C C Buoso E E Racchi M M Govoni S S Memo M M Uberti D D

Cell death & disease 20130207

The role of p53 in neurodegenerative diseases is essentially associated with neuronal death. Recently an alternative point of view is emerging, as altered p53 conformation and impaired protein function have been found in fibroblasts and blood cells derived from Alzheimer's disease patients. Here, using stable transfected SH-SY5Y cells overexpressing APP751wt (SY5Y-APP) we demonstrated that the expression of an unfolded p53 conformation compromised neuronal functionality. In particular, these cel ...[more]

PMID: 23392172

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Project description:BackgroundAlzheimer's disease is the most common cause of dementia and is characterized by amyloid-β plaques, tau neurofibrillary tangles, and neuronal loss. Although neuronal loss is a primary hallmark of Alzheimer's disease, it is known that non-neuronal cell populations are ultimately responsible for maintaining brain homeostasis and neuronal health through neuron-glia and glial cell crosstalk. Many signaling pathways have been proposed to be dysregulated in Alzheimer's disease, including WNT, TGFβ, p53, mTOR, NFkB, and Pi3k/Akt signaling. Here, we predict altered cell-cell communication between glia and neurons.MethodsUsing public snRNA-sequencing data generated from postmortem human prefrontal cortex, we predicted altered cell-cell communication between glia (astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells) and neurons (excitatory and inhibitory). We confirmed interactions in an independent orthogonal dataset. We determined cell-type-specificity using Jaccard Similarity Index and investigated the downstream effects of altered interactions in inhibitory neurons through gene expression and transcription factor activity analyses of signaling mediators. Finally, we determined changes in pathway activity in inhibitory neurons.ResultsCell-cell communication between glia and neurons is altered in Alzheimer's disease in a cell-type-specific manner. As expected, ligands are more cell-type-specific than receptors and targets. We validated 51 ligand-receptor pairs in an independent dataset that included two known Alzheimer's disease risk genes: APP and APOE. 17 (14 upregulated and 3 downregulated in Alzheimer's disease) of the 51 interactions also had the same downstream target gene. Most of the signaling mediators of these interactions were not differentially expressed, however, the mediators that are also transcription factors had differential activity between AD and control. Namely, MYC and TP53, which are associated with WNT and p53 signaling, respectively, had repressor activity in Alzheimer's disease, along with decreased WNT and p53 activity in inhibitory neurons. Additionally, inhibitory neurons had both increased NFkB signaling pathway activity and activator activity of NFIL3, an NFkB signaling-associated transcription factor.ConclusionsCell-cell communication between glia and neurons in Alzheimer's disease is altered in a cell-type-specific manner involving Alzheimer's disease risk genes. Signaling mediators had altered transcription factor activity suggesting altered glia-neuron interactions may dysregulate signaling pathways including WNT, p53, and NFkB in inhibitory neurons.

Dataset Information

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

Publications

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

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