Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
BMC Med. 2023 Jul 13;21(1):254. doi: 10.1186/s12916-023-02931-6.
Schizophrenia and bipolar disorder (BD) are believed to share clinical symptoms, genetic risk, etiological factors, and pathogenic mechanisms. We previously reported that single nucleotide polymorphisms spanning chromosome 3p21.1 showed significant associations with both schizophrenia and BD, and a risk SNP rs2251219 was in linkage disequilibrium with a human specific Alu polymorphism rs71052682, which showed enhancer effects on transcriptional activities using luciferase reporter assays in U251 and U87MG cells.
CRISPR/Cas9-directed genome editing, real-time quantitative PCR, and public Hi-C data were utilized to investigate the correlation between the Alu polymorphism rs71052682 and NISCH. Primary neuronal culture, immunofluorescence staining, co-immunoprecipitation, lentiviral vector production, intracranial stereotaxic injection, behavioral assessment, and drug treatment were used to examine the physiological impacts of Nischarin (encoded by NISCH).
Deleting the Alu sequence in U251 and U87MG cells reduced mRNA expression of NISCH, the gene locates 180 kb from rs71052682, and Hi-C data in brain tissues confirmed the extensive chromatin contacts. These data suggested that the genetic risk of schizophrenia and BD predicted elevated NISCH expression, which was also consistent with the observed higher NISCH mRNA levels in the brain tissues from psychiatric patients compared with controls. We then found that overexpression of NISCH resulted in a significantly decreased density of mushroom dendritic spines with a simultaneously increased density of thin dendritic spines in primary cultured neurons. Intriguingly, elevated expression of this gene in mice also led to impaired spatial working memory in the Y-maze. Given that Nischarin is the target of anti-hypertensive agents clonidine and tizanidine, which have shown therapeutic effects in patients with schizophrenia and patients with BD in preliminary clinical trials, we demonstrated that treatment with those antihypertensive drugs could reduce NISCH mRNA expression and rescue the impaired working memory in mice.
We identify a psychiatric risk gene NISCH at 3p21.1 GWAS locus influencing dendritic spine morphogenesis and cognitive function, and Nischarin may have potentials for future therapeutic development.
精神分裂症和双相情感障碍（BD）被认为具有临床症状、遗传风险、病因和发病机制的相似性。我们之前的研究报告表明，跨越 3p21.1 染色体的单核苷酸多态性与精神分裂症和 BD 均显著相关，风险 SNP rs2251219 与人类特异性 Alu 多态性 rs71052682 呈连锁不平衡，后者在 U251 和 U87MG 细胞中的荧光素酶报告基因检测中显示出转录活性的增强子效应。
利用 CRISPR/Cas9 定向基因组编辑、实时定量 PCR 和公共 Hi-C 数据，研究 Alu 多态性 rs71052682 与 NISCH 之间的相关性。原代神经元培养、免疫荧光染色、共免疫沉淀、慢病毒载体生产、脑内立体定位注射、行为评估和药物治疗用于检测 Nischarin（由 NISCH 编码）的生理影响。
在 U251 和 U87MG 细胞中删除 Alu 序列会降低位于 rs71052682 下游 180kb 的 NISCH 基因的 mRNA 表达，且脑组织中的 Hi-C 数据证实了广泛的染色质接触。这些数据表明，精神分裂症和 BD 的遗传风险预示着 NISCH 表达升高，这与精神科患者脑组织中观察到的 NISCH mRNA 水平高于对照组的情况一致。我们发现，原代培养神经元中 NISCH 的过表达导致蘑菇状树突棘密度显著降低，同时薄树突棘密度增加。有趣的是，该基因在小鼠中的高表达也导致 Y 迷宫中空间工作记忆受损。鉴于 Nischarin 是抗高血压药物可乐定和替扎尼定的靶标，这两种药物在精神分裂症和 BD 的初步临床试验中显示出治疗效果，我们证明了这些抗高血压药物的治疗可以降低小鼠 NISCH mRNA 表达并挽救其受损的工作记忆。
我们在 3p21.1 GWAS 位点发现了一个影响树突棘形态发生和认知功能的精神疾病风险基因 NISCH，Nischarin 可能具有未来治疗开发的潜力。
