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<p>Intracerebral hemorrhage (ICH) incidence increases with age, and neuronal mitochondrial dysfunction and apoptosis post-ICH contribute to severe secondary brain injury. It is of paramount importance to explore molecular targets for protecting against brain injury after ICH. UBA52, a ubiquitin precursor protein, was found to be upregulated in brain tissues of ICH mice. Intracerebral injection of adeno-associated virus type 9 overexpressing UBA52 (AAV9-UBA52) alleviated neurological deficits and brain edema in ICH mice. In vitro and in vivo experiments demonstrated that UBA52 overexpression reduced hemin or ICH-induced apoptosis, reflected in decreased TUNEL-positive cells and reduced caspase-3 and caspase-9 levels. The augmentation of fluorescence intensity in Mitotracker labeling and the reduction of fluorescence intensity in JC-1 staining suggested that UBA52 overexpression mitigated hemin-induced mitochondrial damage. This was further evidenced by increased cellular ATP content and elevated cytochrome <i>c</i> levels located in mitochondria. In vivo findings showed that UBA52 overexpression reduced the quantity of degenerative neurons. UBA52 and NeuN co-localization verified its direct protective effect on neurons. IP-LC/MS and Co-IP assays identified Daxx as a UBA52-interacting protein, with UBA52 promoting Daxx ubiquitination and degradation. Rescue experiments showed Daxx overexpression abolished the protective effect of UBA52 against hemin-induced apoptosis and mitochondrial dysfunction. Collectively, this study demonstrated that UBA52 ameliorates ICH-induced secondary brain injury by promoting Daxx ubiquitination/degradation to inhibit neuronal apoptosis and mitochondrial damage, suggesting UBA52 as a potential protective target for ICH therapy.</p>

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UBA52 Overexpression Ameliorates Intracerebral Hemorrhage-Associated Neuronal Apoptosis and Mitochondrial Dysfunction: A Protective Role in Neurons

  • 期刊论文

  • 发表日期：

    2026年1月19日

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  • Shuainan Ma,
  • Qi Liu,
  • Wei Han,
  • Zhiyi Liu,
  • Sinan Jin,
  • He Wu,
  • Wei Hua

摘要

Intracerebral hemorrhage (ICH) incidence increases with age, and neuronal mitochondrial dysfunction and apoptosis post-ICH contribute to severe secondary brain injury. It is of paramount importance to explore molecular targets for protecting against brain injury after ICH. UBA52, a ubiquitin precursor protein, was found to be upregulated in brain tissues of ICH mice. Intracerebral injection of adeno-associated virus type 9 overexpressing UBA52 (AAV9-UBA52) alleviated neurological deficits and brain edema in ICH mice. In vitro and in vivo experiments demonstrated that UBA52 overexpression reduced hemin or ICH-induced apoptosis, reflected in decreased TUNEL-positive cells and reduced caspase-3 and caspase-9 levels. The augmentation of fluorescence intensity in Mitotracker labeling and the reduction of fluorescence intensity in JC-1 staining suggested that UBA52 overexpression mitigated hemin-induced mitochondrial damage. This was further evidenced by increased cellular ATP content and elevated cytochrome c levels located in mitochondria. In vivo findings showed that UBA52 overexpression reduced the quantity of degenerative neurons. UBA52 and NeuN co-localization verified its direct protective effect on neurons. IP-LC/MS and Co-IP assays identified Daxx as a UBA52-interacting protein, with UBA52 promoting Daxx ubiquitination and degradation. Rescue experiments showed Daxx overexpression abolished the protective effect of UBA52 against hemin-induced apoptosis and mitochondrial dysfunction. Collectively, this study demonstrated that UBA52 ameliorates ICH-induced secondary brain injury by promoting Daxx ubiquitination/degradation to inhibit neuronal apoptosis and mitochondrial damage, suggesting UBA52 as a potential protective target for ICH therapy.