Downregulation by CNNM2 of ATP5MD expression in the 10q24.32 schizophrenia-associated locus involved in impaired ATP production and neurodevelopment
| Autor: | Shufen Li, Zhongju Wang, Cunyou Zhao, Linyan Ye, Bo Guo, Qiyang Li, Bingtao Hao, Hao Zhao, Qiqi Zhuo, Xiuqin Bao, Zhaoqiang Li, Yongchang Zhu, Tengfei Yang |
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| Rok vydání: | 2021 |
| Předmět: |
Psychiatry
0301 basic medicine Genetics Genetics of the nervous system Gene knockdown ATP synthase RC435-571 Locus (genetics) Genome-wide association study Biology Article Chromatin 03 medical and health sciences Psychiatry and Mental health 030104 developmental biology 0302 clinical medicine Downregulation and upregulation Schizophrenia biology.protein Neural development 030217 neurology & neurosurgery Genetic association |
| Zdroj: | NPJ Schizophrenia npj Schizophrenia, Vol 7, Iss 1, Pp 1-11 (2021) |
| ISSN: | 2334-265X |
| DOI: | 10.1038/s41537-021-00159-y |
| Popis: | Genome-wide association studies (GWAS) have accelerated the discovery of numerous genetic variants associated with schizophrenia. However, most risk variants show a small effect size (odds ratio (OR) ATP5MD, encoding an ATP synthase membrane subunit, is observed to be downregulated in schizophrenia by the risk allele of CNNM2-rs1926032 in the schizophrenia-associated 10q24.32 locus. The Atp5md knockout (KO) in mice was associated with abnormal startle reflex and gait, and ATP5MD knockdown (KD) in human induced pluripotent stem cell-derived neurons disrupted the neural development and mitochondrial respiration and ATP production. Moreover, CNNM2-rs1926032 KO could induce downregulation of ATP5MD expression and disruptions of mitochondrial respiration and ATP production. This study constitutes an important mechanistic component that links schizophrenia-associated CNNM2 regions to disruption in energy adenosine system modulation and neuronal function by long-distance chromatin domain downregulation of ATP5MD. This pathogenic mechanism provides therapeutic implications for schizophrenia. |
| Databáze: | OpenAIRE |
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