p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration

Abstract

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.

Role of p53 in the Regulation of Cellular Senescence

“…Neurotoxic effects of astrocytes are mediated by SASP involving pro-inflammatory cytokine secretion (e.g., Il-6), while neuroprotection is mediated by neurotropic growth factors such as NGF [126]. Turnquist et al reported the expression of two isoforms of p53 in astrocytes, ∆133p53 and p53β; in in vitro primary human senescent astrocytes, a decreased expression of the isoform ∆133p53 was reported, and the decreased expression of this isoform, linked to neuroprotection, was attributed to autophagic degradation [127]. These findings suggest that regulatory mechanisms of p53 isoforms may represent a potential target for therapeutic strategies.…”

p53 on the crossroad between regeneration and cancer

“…48 p53 and its isoforms are associated with development of neurodegenerative diseases such as Parkinson's and Alzheimer's because of its induction of cell death in response to stress and interaction with distinct cellular factors that have the ability to facilitate the development of these diseases. 49, 50, 51, 52 …”

Astrocyte senescence in an Alzheimer’s disease mouse model is mediated by TGF-β1 and results in neurotoxicity

“…We suggest that IL-6 in combination with the reduction in VEGF and BDNF plays a part in the impairment of 5xFAD astrocytes to support neurons. In line with this concept, Turnquist et al's study showed that while young astrocytes (early passage) displayed an increase in neuroprotective growth factors, which resulted in normal neurons, there was an increase in IL-6 secretion in senescent astrocytes (late passage) followed by apoptosis of neurons (42). Those authors also reported that brain sections from deceased patients with AD had increased numbers of senescent astrocytes as well as an increase in IL-6 expression (42).…”