Bidirectional interactions between astrocytes and neurons have physiological roles in the central nervous system and an altered 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 regulate 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 regulatory mechanisms are potential targets for therapeutic intervention in neurodegenerative diseases.

• MeSH
• alternativní sestřih MeSH
• Alzheimerova nemoc metabolismus   patologie   MeSH
• amyotrofická laterální skleróza metabolismus   patologie   MeSH
• astrocyty cytologie   účinky léků   metabolismus   MeSH
• autofagie účinky léků   MeSH
• genetické vektory genetika   metabolismus   MeSH
• interleukin-6 genetika   metabolismus   MeSH
• kokultivační techniky MeSH
• kultivované buňky MeSH
• leupeptiny farmakologie   MeSH
• lidé MeSH
• malá interferující RNA metabolismus   MeSH
• mozek metabolismus   patologie   MeSH
• nádorový supresorový protein p53 antagonisté a inhibitory   genetika   metabolismus   MeSH
• neurony cytologie   metabolismus   MeSH
• neuroprotekce fyziologie   MeSH
• protein - isoformy antagonisté a inhibitory   genetika   metabolismus   MeSH
• RNA interference MeSH
• sekvestosom 1 antagonisté a inhibitory   genetika   metabolismus   MeSH
• serin-arginin sestřihové faktory antagonisté a inhibitory   genetika   metabolismus   MeSH
• stárnutí buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH