Molecular signaling pathways underlying schizophrenia
Molecular signaling pathways underlying schizophrenia
Abstract The molecular pathophysiological mechanisms underlying schizophrenia have remained unknown, and no treatment exists for primary prevention. Studies using stem cell-derived neurons have investigated differentially expressed genes (DEGs) and GO and KEGG pathways between patients and controls, but not analyzed data-driven causal molecular pathways involved. We used Ingenuity Pathway Analysis (IPA) to analyze canonical and causal pathways in two different datasets, including patients from Finland and USA. The most significant findings in canonical pathway analysis were observed for glutamate receptor signaling, hepatic fibrosis, and glycoprotein 6 (GP6) pathways in the Finnish dataset, and GP6 and hepatic fibrosis pathways in the US dataset. In data-driven causal pathways, ADCYAP1, ADAMTS, and CACNA genes were involved in the majority of the top 10 pathways differentiating patients and controls in both Finnish and US datasets. In contrast, no dopamine-specific genes were consistently involved. Results from a Finnish nation-wide database showed that the risk of schizophrenia relapse was 41% lower among first-episode patients during the use of losartan, the master regulator of an ADCYAP1, ADAMTS, and CACNA -related pathway, compared to those time periods when the same individual did not use the drug. This association was not attributable to general adherence to drug treatments. The results from the two independent datasets suggest that the GP6 signaling pathway, and the ADCYAP1, ADAMTS, and CACNA -related purine, oxidative stress, and glutamatergic signaling pathways are primary pathophysiological alterations in schizophrenia among patients with European ancestry. While no reproducible dopaminergic alterations were observed, the results imply that agents such as losartan, and ADCYAP1/PACAP -deficit alleviators, such as metabotropic glutamate 2/3 agonist MGS0028 and 5-HT7 antagonists – which have shown beneficial effects in an experimental Adcyap1-/- mouse model for schizophrenia – could be potential treatments before the full manifestation of illness involving dopaminergic abnormalities.
Koskuvi Marja、Vaurio Olli、Koistinaho Jari、Therman Sebastian、Suvisaari Jaana、Cheng Lesley、Trontti Kalevi、Tanskanen Antti、Lehtonen ?¨￠rka、Ojansuu Ilkka、Tiihonen Jari、Taipale Heidi、L?hteenvuo Markku、L?nnqvist Jouko、Cannon Tyrone D.
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland||Neuroscience Center, University of HelsinkiDepartment of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi HospitalA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland||Neuroscience Center, University of HelsinkiMental Health Unit, Department of Public Health Solutions, National Institute for Health and WelfareMental Health Unit, Department of Public Health Solutions, National Institute for Health and WelfareDepartment of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe UniversitySleepWell Research Program and Department of Psychology and Logopedics, Faculty of Medicine, University of HelsinkiDepartment of Clinical Neuroscience, Karolinska Institutet||Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi HospitalA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland||Neuroscience Center, University of HelsinkiDepartment of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi HospitalDepartment of Clinical Neuroscience, Karolinska Institutet||Center for Psychiatry Research, Stockholm City Council||Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi HospitalDepartment of Clinical Neuroscience, Karolinska Institutet||Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital||School of Pharmacy, University of Eastern FinlandDepartment of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi HospitalMental Health Unit, Department of Public Health Solutions, National Institute for Health and Welfare||Department of Psychiatry, University of HelsinkiDepartment of Psychology and Psychiatry, Yale University
神经病学、精神病学基础医学分子生物学
schizophreniastem cellhiPScpathway
Koskuvi Marja,Vaurio Olli,Koistinaho Jari,Therman Sebastian,Suvisaari Jaana,Cheng Lesley,Trontti Kalevi,Tanskanen Antti,Lehtonen ?¨￠rka,Ojansuu Ilkka,Tiihonen Jari,Taipale Heidi,L?hteenvuo Markku,L?nnqvist Jouko,Cannon Tyrone D..Molecular signaling pathways underlying schizophrenia[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2020.06.23.156653.点此复制
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