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MST1 Regulates Neuronal Cell Death via JNK/Casp3 Signaling Pathway in HFD Mouse Brain and HT22 Cells
Mehtab Khan1, Bart P F Rutten2, Myeong Ok Kim3
1Division of Life Science and Applied Life Science (BK21 Plus), College of Natural Sciences, Gyeongsang National University, Jinju 52828, Korea. mehtabneuro@gnu.ac.kr.
Abstract:
Oxidative stress has been considered as the main mediator in neurodegenerative diseases. A high-fat diet (HFD) and metabolic diseases result in oxidative stress generation, leading to various neurodegenerative diseases via molecular mechanisms that remain largely unknown. Protein kinases play an important role in the homeostasis between cell survival and cell apoptosis. The mammalian sterile 20-like kinase-1 (MST1) protein kinase plays an important role in cellular apoptosis in different organ systems, including the central nervous system. In this study, we evaluated the MST1/c-Jun N-terminal kinase (JNK) dependent oxidative damage mediated cognitive dysfunction in HFD-fed mice and stress-induced hippocampal HT22 (mice hippocampal) cells. Our Western blot and immunofluorescence results indicate that HFD and stress-induced hippocampal HT22 cells activate MST1/JNK/Caspase-3 (Casp-3) signaling, which regulates neuronal cell apoptosis and beta-amyloid-cleaving enzyme (BACE1) expression and leads to impaired cognition. Moreover, MST1 expression inhibition by shRNA significantly reduced JNK/Casp-3 signaling. Our in vivo and in vitro experiments mimicking metabolic stress, such as a high-fat diet, hyperglycemia, and an inflammatory response, determined that MST1 plays a key regulatory role in neuronal cell death and cognition, suggesting that MST1 could be a potential therapeutic target for numerous neurodegenerative diseases.
Insights
High-fat diets induce oxidative stress and cognitive decline by activating the MST1/JNK pathway, leading to neuronal apoptosis. Inhibiting MST1 may offer a therapeutic strategy for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Molecular Biology
- Metabolic Diseases
Background:
- Oxidative stress is a key factor in neurodegenerative diseases, often exacerbated by high-fat diets (HFD) and metabolic dysfunction.
- The molecular mechanisms linking metabolic stress to neurodegeneration are not fully understood.
- Protein kinases, like mammalian sterile 20-like kinase-1 (MST1), are crucial in regulating cell survival and apoptosis.
Purpose of the Study:
- To investigate the role of MST1/c-Jun N-terminal kinase (JNK) signaling in oxidative damage-induced cognitive dysfunction in HFD-fed mice and HT22 cells.
- To elucidate the molecular pathways involved in MST1-mediated neuronal apoptosis and cognitive impairment.
Main Methods:
- Utilized high-fat diet (HFD) fed mice and stress-induced hippocampal HT22 cells as in vitro and in vivo models.
- Employed Western blot and immunofluorescence techniques to analyze protein expression and signaling pathways.
- Investigated the effect of MST1 inhibition using short hairpin RNA (shRNA).
Main Results:
- HFD and cellular stress activated the MST1/JNK/Caspase-3 (Casp-3) signaling pathway.
- This activation was linked to increased neuronal apoptosis, elevated beta-amyloid-cleaving enzyme 1 (BACE1) expression, and impaired cognition.
- Inhibition of MST1 significantly attenuated JNK/Casp-3 signaling.
Conclusions:
- MST1 plays a critical role in metabolic stress-induced neuronal cell death and cognitive dysfunction.
- The MST1/JNK/Casp-3 pathway is a key mediator of oxidative damage in neurodegeneration.
- MST1 represents a potential therapeutic target for neurodegenerative diseases associated with metabolic dysfunction.
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