Cellular senescence is a hallmark of normal aging and aging-related syndromes, including the premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS), a rare genetic disorder caused by a single mutation in the LMNA gene that results in the constitutive expression of a truncated splicing mutant of lamin A known as progerin. Progerin accumulation leads to increased cellular stresses including unrepaired DNA damage, activation of the p53 signaling pathway and accelerated senescence. We previously established that the p53 isoforms ∆133p53 and p53β regulate senescence in normal human cells. However, their role in premature aging is unknown. Here we report that p53 isoforms are expressed in primary fibroblasts derived from HGPS patients, are associated with their accelerated senescence and that their manipulation can restore the replication capacity of HGPS fibroblasts. We found that in near-senescent HGPS fibroblasts, which exhibit low levels of ∆133p53 and high levels of p53β, restoration of Δ133p53 expression was sufficient to extend replicative lifespan and delay senescence, despite progerin levels and abnormal nuclear morphology remaining unchanged. Conversely, Δ133p53 depletion or p53β overexpression accelerated the onset of senescence in otherwise proliferative HGPS fibroblasts. Our data indicate that Δ133p53 exerts its role by modulating full-length p53 (FLp53) signaling to extend the replicative lifespan and promotes the repair of spontaneous progerin-induced DNA double-strand breaks (DSBs). We showed that Δ133p53 dominant-negative inhibition of FLp53 occurs directly at the p21/CDKN1A and miR-34a promoters, two p53 senescence-associated genes. In addition, Δ133p53 expression increased the expression of DNA repair RAD51, likely through upregulation of E2F1, a transcription factor that activates RAD51, to promote repair of DSBs. In summary, our data indicate that Δ133p53 modulates p53 signaling to repress progerin-induced early onset of senescence in HGPS cells. Therefore, restoration of ∆133p53 expression may be a novel therapeutic strategy to treat aging-associated phenotypes of HGPS in vivo.

• MeSH
• Time Factors MeSH
• Fibroblasts pathology   physiology   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Tumor Suppressor Protein p53 genetics   physiology   MeSH
• DNA Damage genetics   MeSH
• Aging, Premature genetics   pathology   MeSH
• Progeria genetics   pathology   MeSH
• Protein Isoforms physiology   MeSH
• Cellular Senescence genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Tumor Suppressor Protein p53 MeSH
• Protein Isoforms MeSH
• TP53 protein, human MeSH Browser

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
• Alternative Splicing MeSH
• Alzheimer Disease metabolism   pathology   MeSH
• Amyotrophic Lateral Sclerosis metabolism   pathology   MeSH
• Astrocytes cytology   drug effects   metabolism   MeSH
• Autophagy drug effects   MeSH
• Genetic Vectors genetics   metabolism   MeSH
• Interleukin-6 genetics   metabolism   MeSH
• Coculture Techniques MeSH
• Cells, Cultured MeSH
• Leupeptins pharmacology   MeSH
• Humans MeSH
• RNA, Small Interfering metabolism   MeSH
• Brain metabolism   pathology   MeSH
• Tumor Suppressor Protein p53 antagonists & inhibitors   genetics   metabolism   MeSH
• Neurons cytology   metabolism   MeSH
• Neuroprotection physiology   MeSH
• Protein Isoforms antagonists & inhibitors   genetics   metabolism   MeSH
• RNA Interference MeSH
• Sequestosome-1 Protein antagonists & inhibitors   genetics   metabolism   MeSH
• Serine-Arginine Splicing Factors antagonists & inhibitors   genetics   metabolism   MeSH
• Cellular Senescence MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• benzyloxycarbonylleucyl-leucyl-leucine aldehyde MeSH Browser
• Interleukin-6 MeSH
• Leupeptins MeSH
• RNA, Small Interfering MeSH
• Tumor Suppressor Protein p53 MeSH
• Protein Isoforms MeSH
• Sequestosome-1 Protein MeSH
• Serine-Arginine Splicing Factors MeSH
• SQSTM1 protein, human MeSH Browser
• SRSF3 protein, human MeSH Browser