2021 Fiscal Year Research-status Report
Exploring the novel role of mitochondrial dynamics in schizophrenia
| Project/Area Number |
19K08041
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| Research Institution | University of Fukui |
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Principal Investigator |
岩田 圭子 福井大学, 子どものこころの発達研究センター, 助教 (30415088)
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| Co-Investigator(Kenkyū-buntansha) |
松崎 秀夫 福井大学, 子どものこころの発達研究センター, 教授 (00334970)
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| Project Period (FY) |
2019-04-01 – 2023-03-31
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| Keywords | oligodendrocyte / mitochondria / schizophrenia |
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| Outline of Annual Research Achievements |
In this project, we wish to address the impact of changes in mitochondrial biogenesis on central nervous system (CNS) development (especially the oligodendrocyte differentiation) and animal behavior. Neurons and synapses have long been the dominant focus of neuroscience, informing theories on pathophysiology of psychiatric disorders. However, majority of cells in the brain are not neurons but glial cells. We are performing experiments to address how oligodendrocyte differentiation regulated by mitochondria impacts on the higher brain functions and pathophysiology of schizophrenia (SZ) following our research methodology and approach.
Here, we report new findings by the 3rd year of the project as follows;
First, we identified the novel variant of PGC-1alpha, a transcriptional coactivator, is a key regulator of mitochondrial biogenesis, which was involved in oligodendrocyte differentiation using the human oligodendrocyte cell line. The variant was expressed in the human brain. Intriguingly, it also expressed in human tissues other than the brain. In addition, we performed RNA sequence using human brain samples. (The study has been approved by Fukui University Medical Research Ethics Committee (approval no.2020028).) The expression of the variant was correlated with 2 transcriptional receptors which were involved in cell differentiation.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
From preliminary results, it was predicted that known PGC-1alpha variant was involved in oligodendrocyte differentiation. However, novel PGC-1alpha variant was identified as a regulator of oligodendrocyte differentiation in the human cell line. Therefore, it is needed to identify the novel variant in the mouse brain before generating conditional mutant mice deficient for the variant. For this reason, generation of the conditional mutant mice is a little behind schedule. On the other hand, we were able to use human brain samples and obtained important results for farther research to elucidate roles of novel PGC-1alpha variant on oligodendrocyte differentiation.
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| Strategy for Future Research Activity |
As it is written in Current Status, it is needed to identify the novel variant in the mouse brain before generating conditional mutant mice deficient for the variant. Then, we will generate the conditional mutant mice deficient for the variant specific exon by CRISPR/Cas9 system. Using the mouse, we will elucidate the role of the novel PGC-1alpha variant on oligodendrocyte differentiation and behaviours in vivo following the original plan. In addition, we will elucidate regulatory mechanisms of the novel PGC-1alpha variant in oligodendrocyte differentiation by identifying transcriptional activators and downstream target genes of the variant. We already have had 2 candidates. It is planned that I visit the Lab of CR (Prof. Scorrano), Padova University, Italy and conduct experiments, especially mitochondrial analyses using imaging systems which are available in his Lab, and discuss about the project twice a year. It must be noted that the decision whether to take a passage to Italy needs to be made after assessing COVID-19 situation.
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| Causes of Carryover |
As it is written in Current Status, we could not generate novel variant specific conditional mutant mice, and we have a plan to do it next year. In addition, while it is planned that I visit the Lab of CR (Prof. Scorrano), Padova University, Italy twice a year but I could not do it because of the COVID-19 situation.
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[Journal Article] Dietary spermidine improves cognitive function2021
Author(s)
Schroeder S, Hofer SJ, Zimmermann A, Pechlaner R, Dammbrueck C, Pendl T, Marcello GM, Pogatschnigg V, Bergmann M, Muller M, Gschiel V, Ristic S, Tadic J, Iwata K,......Racz B, Kiechl S, Eisenberg T, Madeo F.
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Journal Title
Cell Reports
Volume: 35
Pages: 108985～108985
DOI
Peer Reviewed / Open Access
