Abstract
Neuropsychiatric diseases, such as schizophrenia and mood disorders, pose a social and economic burden for society. They have an estimated prevalence of 12% and account for 15.2% of early occupational retirement in Europe. Healthcare costs related to treatment-resistant cases can soar with the predicated escalation in prevalence. Unfortunately, many patients are resistant to current treatments, or relapse. To improve this situation, there is a strong need for increased basic research in this area. This is especially true when aiming for a personalized treatment approach.
c-Jun N-terminal kinases (JNKs) are central sensors of cellular stress in the brain. They are activated by a wide range of stimuli, including glutamate and endocrine stress. In turn, they activate negative feedback pathways to maintain homeostatic regulation. JNKs play a crucial role during brain development, being essential for neural tube closure. Specifically, JNK1 influences tangential and radial migration, as well as dendritic arborization and spine stability. JNK1 regulates mood-related behaviors, and inhibitors have anxiolytic- and antidepressant-like effects. Surprisingly, there is a lack of detailed understanding of JNK substrates as a whole, and how their phosphorylation by JNK1 affects their function remains relatively uncharted territory in the field.
This thesis began with an investigation of JNK1’s impact on the phosphoproteome of the mouse brain, where advanced phosphoproteomic analysis was employed to assess changes in protein phosphorylation. The results revealed that 10% of brain phosphoproteins are significantly altered in Jnk1-/- brain, and these proteins are highly enriched for schizophrenia proteins. Pathway enrichment analysis suggested that JNK1 regulates NMDA receptor trafficking. This prediction was validated experimentally as part of the thesis work. In addition to NMDA receptors, we also found that GABAΑ receptor trafficking was regulated by JNK1. In addition, we found that JNK1 regulates
dendritic spine morphology. These findings are relevant for investigations of new schizophrenia treatments, and suggest a convergence on the JNK pathway. In parallel, we identified that GIT1 is directly phosphorylated by JNK1, and this phosphorylation controls GABAA receptor trafficking. The detailed mechanism whereby JNK1 phosphorylation of GIT1 represses GABAAR cell-surface expression is a major finding of the work. It provides a mechanism for neurons to respond to stress and regulate neuronal excitability. Overall, the results offer new molecular insights into the role of JNK1 in regulating dendritic spine morphology and receptor trafficking, while altering excitability.
c-Jun N-terminal kinases (JNKs) are central sensors of cellular stress in the brain. They are activated by a wide range of stimuli, including glutamate and endocrine stress. In turn, they activate negative feedback pathways to maintain homeostatic regulation. JNKs play a crucial role during brain development, being essential for neural tube closure. Specifically, JNK1 influences tangential and radial migration, as well as dendritic arborization and spine stability. JNK1 regulates mood-related behaviors, and inhibitors have anxiolytic- and antidepressant-like effects. Surprisingly, there is a lack of detailed understanding of JNK substrates as a whole, and how their phosphorylation by JNK1 affects their function remains relatively uncharted territory in the field.
This thesis began with an investigation of JNK1’s impact on the phosphoproteome of the mouse brain, where advanced phosphoproteomic analysis was employed to assess changes in protein phosphorylation. The results revealed that 10% of brain phosphoproteins are significantly altered in Jnk1-/- brain, and these proteins are highly enriched for schizophrenia proteins. Pathway enrichment analysis suggested that JNK1 regulates NMDA receptor trafficking. This prediction was validated experimentally as part of the thesis work. In addition to NMDA receptors, we also found that GABAΑ receptor trafficking was regulated by JNK1. In addition, we found that JNK1 regulates
dendritic spine morphology. These findings are relevant for investigations of new schizophrenia treatments, and suggest a convergence on the JNK pathway. In parallel, we identified that GIT1 is directly phosphorylated by JNK1, and this phosphorylation controls GABAA receptor trafficking. The detailed mechanism whereby JNK1 phosphorylation of GIT1 represses GABAAR cell-surface expression is a major finding of the work. It provides a mechanism for neurons to respond to stress and regulate neuronal excitability. Overall, the results offer new molecular insights into the role of JNK1 in regulating dendritic spine morphology and receptor trafficking, while altering excitability.
| Original language | English |
|---|---|
| Supervisors/Advisors |
|
| Place of Publication | Åbo |
| Publisher | |
| Print ISBNs | 9978-952-12-4624-1 |
| Electronic ISBNs | 978-952-12-4625-8 |
| Publication status | Published - 2025 |
| MoE publication type | G5 Doctoral dissertation (article) |