Abstract
Intracerebral hemorrhage (ICH) is a common neurological condition associated with high disability and mortality. Alterations in protein ubiquitination have emerged as a key mechanism in the pathogenesis of neurological diseases. Here, we investigated the effects of the E3 ubiquitin ligase ring finger protein 34 (RNF34) on neurological deficits and brain injury in ICH mice. An ICH model was established via intracerebral injection of autologous blood into wild-type and RNF34 transgenic mice. Brain injury, neurological function, neuronal activity, and oxidative stress levels were measured, respectively. The underlying mechanisms were explored by molecular and cellular approaches. Our results showed that RNF34 overexpression in mice significantly aggravated the ICH-induced memory impairment, brain edema, infarction, hematoma volume, and loss of neuronal activity. RNF34 and oxidative stress levels gradually increased from 6 to 48 h after the ICH challenge and were positively correlated. The ICH-induced increase in intracellular ROS, superoxide anion, and mROS generation and the decrease in adenosine triphosphate production were exacerbated in RNF34 transgenic mice, but NADPH oxidase activity was unaffected. Moreover, RNF34 upregulation potentiated the ICH-induced decrease in PGC-1α, UCP2, and MnSOD expressions. RNF34 interacted with PGC-1α and targeted it for ubiquitin-dependent degradation. This study reveals that RNF34 exacerbates neurological deficits and brain injury by facilitating PGC-1α protein degradation and promoting mitochondrial dysfunction-mediated oxidative stress.
Highlights
Intracerebral hemorrhage (ICH) is a common neurological condition associated with high disability and mortality
ring finger protein 34 (RNF34) has been shown to be an E3 ubiquitin ligase targeting for peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), which is critical for oxidative stress, mitochondrial biogenesis and cell metabolism[12,14]
The results of the rotarod test showed that ICH significantly impaired the performance of the mice, which was more pronounced in transgenic mice (Fig. 1D)
Summary
Intracerebral hemorrhage (ICH) is a common neurological condition associated with high disability and mortality. We investigated the effects of the E3 ubiquitin ligase ring finger protein 34 (RNF34) on neurological deficits and brain injury in ICH mice. This study reveals that RNF34 exacerbates neurological deficits and brain injury by facilitating PGC-1α protein degradation and promoting mitochondrial dysfunction-mediated oxidative stress. Previous studies suggested that hematoma can induce glutamate release and subsequently cause oxidative stress and mitochondrial dysfunction, which play an important role in brain injury after ICH4–7. RNF34 is an E3 ubiquitin ligase that regulates protein substrates by post-translational modification[12] It is associated with regulating postsynaptic γ2-GABAAR clustering and GABAergic synaptic innervation in hippocampal neurons[13], indicating the importance of RNF34 in regulating neurological function. We hypothesize that RNF34 potentiates neurological deficits and brain injury induced by ICH through oxidative stress and mitochondrial dysfunction. Our findings suggest that RNF34 may be a novel molecular target for the treatment of ICH
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