Nuclear WRAP53 promotes neuronal survival and functional recovery after stroke

Sánchez‐Morán, Irene; Rodrı́guez, Cristina; Lapresa, Rebeca; Agulla, Jesús; Sobrino, Tomás; Castillo, José; Bolaños, Juan P.; Almeida, Ángeles

doi:10.1126/sciadv.abc5702

Cited by 16 publications

(14 citation statements)

References 62 publications

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“…Substitution of arginine (Arg68) for glycine (Gly68) affects protein function and location within the cell. These results confirm, once again, that controlling neuronal susceptibility to ischemia‐induced apoptosis promotes better functional recovery after stroke as patients carrying the SNP showed less infarct volume and better prognosis 59 (Figure 3). The study of these mechanisms underlying neuronal death by apoptosis will therefore help to better manage patients in order to provide them with better functional recovery after stroke and might explain why patients who initially show similar symptoms and lesion volumes may improve dramatically or worsen after stroke.…”

Section: Interaction Of P53 With the Mitochondria Regulates Neuronal supporting

confidence: 75%

“…WRAP53 cellular localization is essential for its prosurvival function. While mitochondrial sequestration circumvents the WRAP53 neuroprotective role in ischemic neurons, nuclear WRAP53 drives the repair of neuronal DNA breaks after ischemic damage, determining neuronal survival and better functional outcome of stroke patients 59 …”

Section: An Overview Of P53 In Strokementioning

confidence: 99%

“…The impact of genetic susceptibility to apoptosis, and specifically p53‐related mutations, has also proven to be crucial in stroke prognosis 4,30,42,59,66 . Several SNP and sequence variations at the human Tp53 gene have been described so far.…”

Section: Interaction Of P53 With the Mitochondria Regulates Neuronal mentioning

confidence: 99%

“…Different mechanisms but the same consequences were observed when the Wrap53 gene, in close proximity to p53, is mutated. A nonsynonymous SNP in codon 68 of the first coding exon of Wrap53 c.202C > G (rs2287499) promotes WRAP53 accumulation in the nucleus, leading to DNA repair after ischemia 59 . Substitution of arginine (Arg68) for glycine (Gly68) affects protein function and location within the cell.…”

Section: Interaction Of P53 With the Mitochondria Regulates Neuronal mentioning

confidence: 99%

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Mitochondrial–nuclear p53 trafficking controls neuronal susceptibility in stroke

2021

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Stroke is a major cause of death and long‐term disability in the adult. Neuronal apoptosis plays an essential role in the pathophysiology of ischemic brain damage and impaired functional recovery after stroke. The tumor suppressor protein p53 regulates key cellular processes, including cell cycle arrest, DNA repair, senescence, and apoptosis. Under cellular stress conditions, p53 undergoes post‐translational modifications, which control protein localization, stability, and proapoptotic activity. After stroke, p53 rapidly accumulates in the ischemic brain, where it activates neuronal apoptosis through both transcriptional‐dependent and ‐independent programs. Over the last years, subcellular localization of p53 has emerged as an important regulator of ischemia‐induced neuronal apoptosis. Upon an ischemic insult, p53 rapidly translocates to the mitochondria and interacts with B‐cell lymphoma‐2 family proteins, which activate the mitochondrial apoptotic program, with higher efficacy than through its activity as a transcription factor. Moreover, the identification of a human single nucleotide polymorphism at codon 72 of the Tp53 gene that controls p53 mitochondrial localization and cell susceptibility to apoptosis supports the important role of the p53 mitochondrial program in neuronal survival and functional recovery after stroke. In this article, we review the relevance of mitochondrial and nuclear localization of p53 on neuronal susceptibility to cerebral ischemia and its impact on functional outcome of stroke patients.

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Section: Interaction Of P53 With the Mitochondria Regulates Neuronal supporting

confidence: 75%

Section: An Overview Of P53 In Strokementioning

confidence: 99%

Section: Interaction Of P53 With the Mitochondria Regulates Neuronal mentioning

confidence: 99%

Section: Interaction Of P53 With the Mitochondria Regulates Neuronal mentioning

confidence: 99%

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Mitochondrial–nuclear p53 trafficking controls neuronal susceptibility in stroke

2021

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“…The balance between pro- and antiapoptotic signals is fundamental to ensure neuronal survival after ischemia [ 3 , 33 , 38 , 42 , 43 , 44 ]. Although the relevance of such events has been shown in both hemorrhagic and ischemic in vivo stroke models [ 43 , 45 ], the mechanisms that regulate these signaling pathways are not yet fully understood in the context of ischemic tolerance.…”

Section: Discussionmentioning

confidence: 99%

Preconditioning-Activated AKT Controls Neuronal Tolerance to Ischemia through the MDM2–p53 Pathway

Barrio

Vecino

Sánchez‐Morán

et al. 2021

IJMS

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One of the most important mechanisms of preconditioning-mediated neuroprotection is the attenuation of cell apoptosis, inducing brain tolerance after a subsequent injurious ischemia. In this context, the antiapoptotic PI3K/AKT signaling pathway plays a key role by regulating cell differentiation and survival. Active AKT is known to increase the expression of murine double minute-2 (MDM2), an E3-ubiquitin ligase that destabilizes p53 to promote the survival of cancer cells. In neurons, we recently showed that the MDM2–p53 interaction is potentiated by pharmacological preconditioning, based on subtoxic stimulation of NMDA glutamate receptor, which prevents ischemia-induced neuronal apoptosis. However, whether this mechanism contributes to the neuronal tolerance during ischemic preconditioning (IPC) is unknown. Here, we show that IPC induced PI3K-mediated phosphorylation of AKT at Ser473, which in turn phosphorylated MDM2 at Ser166. This phosphorylation triggered the nuclear stabilization of MDM2, leading to p53 destabilization, thus preventing neuronal apoptosis upon an ischemic insult. Inhibition of the PI3K/AKT pathway with wortmannin or by AKT silencing induced the accumulation of cytosolic MDM2, abrogating IPC-induced neuroprotection. Thus, IPC enhances the activation of PI3K/AKT signaling pathway and promotes neuronal tolerance by controlling the MDM2–p53 interaction. Our findings provide a new mechanistic pathway involved in IPC-induced neuroprotection via modulation of AKT signaling, suggesting that AKT is a potential therapeutic target against ischemic injury.

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USP25 Inhibits Neuroinflammatory Responses After Cerebral Ischemic Stroke by Deubiquitinating TAB2

Li,

Liu,

Lambertsen

et al. 2023

Advanced Science

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Cerebral ischemic stroke is a leading cause of morbidity and mortality globally. However, the mechanisms underlying ischemic stroke injury remain poorly understood. Here, it is found that deficiency of the ubiquitin‐specific protease USP25 significantly aggravate ischemic stroke injury in mice. USP25 has no impact on neuronal death under hypoxic conditions, but reduced ischemic stroke‐induced neuronal loss and neurological deficits by inhibiting microglia‐mediated neuroinflammation. Mechanistically, USP25 restricts the activation of NF‐κB and MAPK signaling by regulating TAB2. As a deubiquitinating enzyme, USP25 removeds K63‐specific polyubiquitin chains from TAB2. AAV9‐mediated TAB2 knockdown ameliorates ischemic stroke injury and abolishes the effect of USP25 deletion. In both mouse and human brains, USP25 is markedly upregulated in microglia in the ischemic penumbra, implying a clinical relevance of USP25 in ischemic stroke. Collectively, USP25 is identified as a critical inhibitor of ischemic stroke injury and this data suggest USP25 may serve as a therapeutic target for ischemic stroke.

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Nuclear WRAP53 promotes neuronal survival and functional recovery after stroke

Cited by 16 publications

References 62 publications

Mitochondrial–nuclear p53 trafficking controls neuronal susceptibility in stroke

Mitochondrial–nuclear p53 trafficking controls neuronal susceptibility in stroke

Preconditioning-Activated AKT Controls Neuronal Tolerance to Ischemia through the MDM2–p53 Pathway

USP25 Inhibits Neuroinflammatory Responses After Cerebral Ischemic Stroke by Deubiquitinating TAB2

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