Unravelling the impact of QRICH1 modulation on endoplasmic reticulum stress and neuronal apoptosis in traumatic brain injury.

Abstract

Background: Traumatic brain injury (TBI) is a major public health concern with high morbidity and mortality rates. Secondary brain injury, marked by inflammatory responses and apoptosis, worsens TBI outcomes. The endoplasmic reticulum stress (ERS) response has been implicated in secondary brain injury, with Glutamine Rich 1 Gene (QRICH1) emerging as a potential mediator. However, the precise role of QRICH1 in TBI pathogenesis and its therapeutic implications remain unclear.

Methods: Controlled cortical impact mouse and Lipopolysaccharide-stimulated primary neuron models were used. Behavioral assessments, including the modified Garcia score, Y-maze test, and open-field test, were used to evaluate postoperative recovery in mice. QRICH1 neuron conditional knockout (cKO) mice were used to assess QRICH1 function, whereas adeno-associated virus (AAV)-mediated gene manipulation was used to modulate QRICH1 expression in cortical neurons.

Results: QRICH1 expression was upregulated in the brain tissue of TBI mice, particularly 24 h post-injury, as shown by western blot analysis and immunofluorescence staining. QRICH1 is localized within neuronal nuclei, suggesting a role in cellular stress responses. QRICH1 cKO improved behavioral outcomes post-TBI, whereas AAV-mediated QRICH1 overexpression exacerbated secondary brain injury, characterized by increased ERS-related protein expression and neuronal death. Conversely, AAV-mediated QRICH1 knockdown reduced secondary brain injury as evidenced by decreased ERS-related protein expression and neuronal death.

Conclusion: QRICH1 plays a critical role in exacerbating ERS and apoptosis, and influences neuronal fate in secondary brain injury. Its involvement in the ERS pathway and in the induction of neuronal apoptosis post-TBI highlights QRICH1 as a potential therapeutic target for TBI treatment.