p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration

• Published in: Cell death and differentiation Vol. 23; no. 9; pp. 1515 - 1528
• Main Authors: Turnquist, C, Horikawa, I, Foran, E, Major, E O, Vojtesek, B, Lane, D P, Lu, X, Harris, B T, Harris, C C
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.09.2016
• Subjects: Alternative Splicing; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Astrocytes - cytology; Astrocytes - drug effects; Astrocytes - metabolism; Autophagy - drug effects; Brain - metabolism; Brain - pathology; Cells, Cultured; Cellular Senescence; Coculture Techniques; Genetic Vectors - genetics; Genetic Vectors - metabolism; Humans; Insulin-like growth factors; Interleukin-6 - genetics; Interleukin-6 - metabolism; Leupeptins - pharmacology; Neurodegeneration; Neurons - cytology; Neurons - metabolism; Neuroprotection - physiology; Original Paper; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - genetics; Protein Isoforms - metabolism; RNA Interference; RNA, Small Interfering - metabolism; Sequestosome-1 Protein - antagonists & inhibitors; Sequestosome-1 Protein - genetics; Sequestosome-1 Protein - metabolism; Serine-Arginine Splicing Factors - antagonists & inhibitors; Serine-Arginine Splicing Factors - genetics; Serine-Arginine Splicing Factors - metabolism; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Washington DC; United States > US; Singapore
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2016.37

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.