p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00209805%3A_____%2F16%3AN0000029" target="_blank" >RIV/00209805:_____/16:N0000029 - isvavai.cz</a>

Result on the web

<a href="http://www.nature.com/cdd/journal/v23/n9/pdf/cdd201637a.pdf" target="_blank" >http://www.nature.com/cdd/journal/v23/n9/pdf/cdd201637a.pdf</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/cdd.2016.37" target="_blank" >10.1038/cdd.2016.37</a>

Result language

angličtina

Original language name

p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration

Original language description

Bidirectional interactions between astrocytes and neurons have physiological roles in the central nervous system and an Alfred state or dysfunction of such interactions may be associated with neurodegenerative diseases, such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). Astrocytes exert structural, metabolic and functional effects on neurons, which can be either neurotoxic or neuroprotective. Their neurotoxic effect is mediated via the senescence-associated secretory phenotype (SASP) involving pro-inflammatory cytokines (e.g., IL-6), while their neuroprotective effect is attributed to neurotrophic growth factors (e.g., NGF). We here demonstrate that the p53 isoforms Δ133p53 and p53β are expressed in astrocytes and regulace their toxic and protective effects on neurons. Primary human astrocytes undergoing cellular senescence upon serial passaging in vitro showed diminished expression of Δ133p53 and increased p53β, which were attributed to the autophagic degradation and the SRSF3-mediated alternative RNA splicing, respectively. Early-passage astrocytes with Δ133p53 knockdown or p53β overexpression were induced to show SASP and to exert neurotoxicity in co-culture with neurons. Restored expression of Δ133p53 in near-senescent, otherwise neurotoxic astrocytes conferred them with neuroprotective activity through repression of SASP and induction of neurotrophic growth factors. Brain tissues from AD and ALS patients possessed increased numbers of senescent astrocytes and, like senescent astrocytes in vitro, showed decreased Δ133p53 and increased p53β expression, supporting that our in vitro findings recapitulate in vivo pathology of these neurodegenerative diseases. Our finding that Δ133p53 enhances the neuroprotective function of aged and senescent astrocytes suggests that the p53 isoforms and their regulátory mechanisms are potential targets for therapeutic intervention in neurodegenerative diseases.

Czech name

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Czech description

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Type

J_x - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

CEP classification

EB - Genetics and molecular biology

OECD FORD branch

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Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2016

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Cell Death and Differentiation

ISSN

1350-9047

e-ISSN

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Volume of the periodical

23

Issue of the periodical within the volume

9

Country of publishing house

GB - UNITED KINGDOM

Number of pages

14

Pages from-to

1515-1528

UT code for WoS article

000381072800009

EID of the result in the Scopus database

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