14-3-3γ and Neuroglobin are New Intrinsic Protective Factors for Cerebral Ischemia

Dong, Yan; Zhao, Rui; Chen, Xiao Qian; Yu, Albert Cheung Hoi

doi:10.1007/s12035-010-8142-4

Cited by 29 publications

(21 citation statements)

References 122 publications

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“…41 In neurons, 14-3-3γ protein appears to contribute to neuronal vulnerability during oxidative stress 42 and increased levels promote astrocyte survival, whereas decreased levels result in increased apoptotic loss under ischemia. 43 YWHAG resides on chromosome 7q11.23, along with several genes, and haploinsufficiency of this region results in William–Beuren syndrome, which includes a specific mental retardation profile, distinctive dysmorphic features and supravalvular aortic stenosis. 44 Interestingly, zebrafish knocked down for YWHAG have reduced brain size and an increased diameter of the heart tube.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of severity in multiple sclerosis

Briggs¹,

Shao²,

Goldstein³

et al. 2011

Genes Immun

105

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Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system with a strong genetic component. Several lines of evidence support a strong role for genetic factors influencing both disease susceptibility and clinical outcome in MS. Identification of genetic variants that distinguish particular disease subgroups and/or predict a severe clinical outcome is critical to further our understanding of disease mechanisms and guide development of effective therapeutic approaches. We studied 1470 MS cases and performed a genome-wide association study of more than 2.5 million single-nucleotide polymorphisms to identify loci influencing disease severity, measured using the MS severity score (MSSS), a measure of clinical disability. Of note, no single result achieved genome-wide significance. Furthermore, variants within previously confirmed MS susceptibility loci do not appear to influence severity. Although bioinformatic analyses highlight certain pathways that are over-represented in our results, we conclude that the genetic architecture of disease severity is likely polygenic and comprised of modest effects, similar to what has been described for MS susceptibility, to date. However, a role for major effects of rare variants cannot be excluded. Importantly, our results also show the MSSS, when considered as a binary or continuous phenotype variable is by comparison a stable outcome.

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Section: Discussionmentioning

confidence: 99%

Genome-wide association study of severity in multiple sclerosis

Briggs¹,

Shao²,

Goldstein³

et al. 2011

Genes Immun

105

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show abstract

“…For example, it is well known that astrocytes and neurons respond differently to ischemic insults via distinct mechanisms. 10 Theoretically, protecting all types of brain cells simultaneously is required for stroke treatment. 2 Thus, finding the key protective molecules conserved in brain cells and understanding clearly their protective mechanisms is required for future development of effective cytoprotective drugs and treatments.…”

mentioning

confidence: 99%

Selective 14-3-3γ induction quenches p-β-catenin Ser37/Bax-enhanced cell death in cerebral cortical neurons during ischemia

Lai

Zheng

et al. 2014

Cell Death Dis

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Ischemia-induced cell death is a major cause of disability or death after stroke. Identifying the key intrinsic protective mechanisms induced by ischemia is critical for the development of effective stroke treatment. Here, we reported that 14-3-3γ was a selective ischemia-inducible survival factor in cerebral cortical neurons reducing cell death by downregulating Bax depend direct 14-3-3γ/p-β-catenin Ser37 interactions in the nucleus. 14-3-3γ, but not other 14-3-3 isoforms, was upregulated in primary cerebral cortical neurons upon oxygen–glucose deprivation (OGD) as measured by quantitative PCR, western blot and fluorescent immunostaining. The selective induction of 14-3-3γ in cortical neurons by OGD was verified by the in vivo ischemic stroke model. Knocking down 14-3-3γ alone or inhibiting 14-3-3/client interactions was sufficient to induce cell death in normal cultured neurons and exacerbate OGD-induced neuronal death. Ectopic overexpression of 14-3-3γ significantly reduced OGD-induced cell death in cultured neurons. Co-immunoprecipitation and fluorescence resonance energy transfer demonstrated that endogenous 14-3-3γ bound directly to more p-β-catenin Ser37 but not p-Bad, p-Ask-1, p-p53 and Bax. During OGD, p-β-catenin Ser37 but not p-β-catenin Ser45 was increased prominently, which correlated with Bax elevation in cortical neurons. OGD promoted the entry of 14-3-3γ into the nuclei, in correlation with the increase of nuclear p-β-catenin Ser37 in neurons. Overexpression of 14-3-3γ significantly reduced Bax expression, whereas knockdown of 14-3-3γ increased Bax in cortical neurons. Abolishing β-catenin phosphorylation at Ser37 (S37A) significantly reduced Bax and cell death in neurons upon OGD. Finally, 14-3-3γ overexpression completely suppressed β-catenin-enhanced Bax and cell death in neurons upon OGD. Based on these data, we propose that the 14-3-3γ/p-β-catenin Ser37/Bax axis determines cell survival or death of neurons during ischemia, providing novel therapeutic targets for ischemic stroke as well as other related neurological diseases.

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“…9). There is growing interest in Ywhag as a mediator of neuroprotection in cerebral ischemia (Dong et al 2010) and the observed decrease in its expression is consistent with the activation of cell death pathways. Additionally, up-regulation of Ywhaq has been observed in amyotrophic lateral sclerosis patients (Malaspina et al 2000), and has been found to be necessary for autophagy (Wang et al 2010).…”

Section: Interaction Network Analysismentioning

confidence: 90%