NQO1 regulates expression and alternative splicing of apoptotic genes associated with Alzheimer's disease in PC12 cells

Abstract

Purpose: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive dysfunction. Quinone oxidoreductase 1 (NQO1) is an antioxidant enzyme that plays an important role in controlling cellular redox state, whose expression is altered in the brain tissues of AD patients. In addition to its traditional antioxidant effects, NQO1 also acts as a multifunctional RNA-binding protein involved in posttranscriptional regulation. Whether the RNA-binding activity of NQO1 influences AD pathology has not been investigated yet. Methods:The RNA-binding functions of NQO1 in rat pheochromocytoma (PC12) cells were investigated using siRNA knockdown followed by total RNA sequencing. Reverse transcription quantitative polymerase chain reaction was performed to explore the impact of NQO1 on the transcription and alternative splicing of apoptotic genes.Results: NQO1 knockdown led to a significant increase in cellular apoptosis. Genes involved in certain apoptosis pathways, such as positive regulation of apoptotic processes and mitogen-activated protein kinase signaling, were under global transcriptional and alternative splicing regulation. NQO1 regulated the transcription of apoptotic genes Cryab, Lgmn, Ngf, Apoe, Brd7, and Stat3, as well as the alternative splicing of apoptotic genes BIN1, Picalm, and Fyn. Conclusion:Our findings suggest that NQO1 participates in the pathology of AD by regulating the expression and alternative splicing of the genes involved in apoptosis. These results extend our understanding of NQO1 in apoptotic pathways at the posttranscriptional level in AD.

Impact of NQO1 dysregulation in CNS disorders

“…Long-term administration of Nrf2 inducer enhances NQO1 expression and prevents the onset of cognitive dysfunction by inhibiting oxidative stress and neuroinflammation in a knockdown mouse model of AD [ 117 ]. NQO1 has been found to posttranscriptionally regulate numerous genes involved in apoptosis, and massive neuronal death due to apoptosis is a well-known characteristic of AD pathophysiology [ 118 ]. The presence of C609T polymorphism resulted in significantly faster aggregation kinetics of amyloid-β (Aβ)1–42 than with wild-type NQO1.…”

“…The upregulation of NQO1 in hippocampal pyramidal cells of subjects with AD suggested that NQO1 may be involved in the brain neuroprotective mechanism that is activated in response to the pathological processes of AD [ 127 ]. However, another investigation reported that approximately half of patients with AD may lack NQO1 expression in the hippocampus due to a C609T polymorphism [ 72 , 118 ]. It has been suggested that the age-dependent accumulation of NQO1 may be impaired in individuals with AD.…”

“…This triggers the activation of diverse cellular defense mechanisms and initiates the activation of numerous anti-oxidative stress genes. This coordinated response serves as a protective mechanism against cell damage and could be used as a therapeutic approach for various pathologies, including those affecting the central nervous system well-known characteristic of AD pathophysiology [118].…”