p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration.
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.
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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Turnquist
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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I
Horikawa
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
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E
Foran
Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
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Major
Regional Centre for Applied and Molecular Oncology, Masaryk Memorial Cancer Institute, Brno 65653, Czech Republic.
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B
Vojtesek
p53 Laboratory, Biomedical Sciences Institutes (A*STAR), Singapore 138648, Singapore.
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Lane
Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
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Lu
Department of Neurology, Georgetown University Medical Center, Washington DC 20007, USA.|Department of Pathology, Georgetown University Medical Center, Washington DC 20007, USA.
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Harris
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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Harris
D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D016922:Cellular Senescence; D018920:Coculture Techniques; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D000066829:Neuroprotection / Q000502:physiology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D000071456:Sequestosome-1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D015850:Interleukin-6; D007976:Leupeptins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; C099718:SQSTM1 protein, human; C491388:SRSF3 protein, human; D000071456:Sequestosome-1 Protein; D016159:Tumor Suppressor Protein p53; D000068103:Serine-Arginine Splicing Factors; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde