{"title":"致病性 SHQ1 变异会导致神经元发育和多巴胺能通路中断。","authors":"","doi":"10.1016/j.expneurol.2024.114968","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Compound heterozygous variants of <em>SHQ1</em>, an assembly factor of H/ACA ribonucleoproteins (RNPs) involved in critical biological pathways, have been identified in patients with developmental delay, dystonia, epilepsy, and microcephaly. We investigated the role of SHQ1 in brain development and movement disorders.</div></div><div><h3>Methods</h3><div><em>SHQ1</em> expression was knocked down using short-hairpin RNA (shRNA) to investigate its effects on neurons. <em>Shq1</em> shRNA and cDNA of WT and mutant <em>SHQ1</em> were also introduced into neural progenitors in the embryonic mouse cortex through <em>in utero</em> electroporation. Co-immunoprecipitation was performed to investigate the interaction between SHQ1 and DKC1, a core protein of H/ACA RNPs.</div></div><div><h3>Results</h3><div>We found that SHQ1 was highly expressed in the developing mouse cortex. <em>SHQ1</em> knockdown impaired the migration and neurite morphology of cortical neurons during brain development. Additionally, <em>SHQ1</em> knockdown impaired neurite growth and sensitivity to glutamate toxicity <em>in vitro</em>. There was also increased dopaminergic function upon <em>SHQ1</em> knockdown, which may underlie the increased glutamate toxicity of the cells. Most SHQ1 variants attenuated their binding ability toward DKC1, implying <em>SHQ1</em> variants may influence brain development by disrupting the assembly and biogenesis of H/ACA RNPs.</div></div><div><h3>Conclusions</h3><div>SHQ1 plays an essential role in brain development and dopaminergic function by upregulating dopaminergic pathways and regulating the behaviors of neural progenitors and their neuronal progeny, potentially leading to dystonia and developmental delay in patients. Our study provides insights into the functions of SHQ1 in neuronal development and dopaminergic function, providing a possible pathogenic mechanism for H/ACA RNPs-related disorders.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6000,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pathogenic SHQ1 variants result in disruptions to neuronal development and the dopaminergic pathway\",\"authors\":\"\",\"doi\":\"10.1016/j.expneurol.2024.114968\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div>Compound heterozygous variants of <em>SHQ1</em>, an assembly factor of H/ACA ribonucleoproteins (RNPs) involved in critical biological pathways, have been identified in patients with developmental delay, dystonia, epilepsy, and microcephaly. We investigated the role of SHQ1 in brain development and movement disorders.</div></div><div><h3>Methods</h3><div><em>SHQ1</em> expression was knocked down using short-hairpin RNA (shRNA) to investigate its effects on neurons. <em>Shq1</em> shRNA and cDNA of WT and mutant <em>SHQ1</em> were also introduced into neural progenitors in the embryonic mouse cortex through <em>in utero</em> electroporation. Co-immunoprecipitation was performed to investigate the interaction between SHQ1 and DKC1, a core protein of H/ACA RNPs.</div></div><div><h3>Results</h3><div>We found that SHQ1 was highly expressed in the developing mouse cortex. <em>SHQ1</em> knockdown impaired the migration and neurite morphology of cortical neurons during brain development. Additionally, <em>SHQ1</em> knockdown impaired neurite growth and sensitivity to glutamate toxicity <em>in vitro</em>. There was also increased dopaminergic function upon <em>SHQ1</em> knockdown, which may underlie the increased glutamate toxicity of the cells. Most SHQ1 variants attenuated their binding ability toward DKC1, implying <em>SHQ1</em> variants may influence brain development by disrupting the assembly and biogenesis of H/ACA RNPs.</div></div><div><h3>Conclusions</h3><div>SHQ1 plays an essential role in brain development and dopaminergic function by upregulating dopaminergic pathways and regulating the behaviors of neural progenitors and their neuronal progeny, potentially leading to dystonia and developmental delay in patients. Our study provides insights into the functions of SHQ1 in neuronal development and dopaminergic function, providing a possible pathogenic mechanism for H/ACA RNPs-related disorders.</div></div>\",\"PeriodicalId\":12246,\"journal\":{\"name\":\"Experimental Neurology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2024-09-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental Neurology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0014488624002942\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Neurology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0014488624002942","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Pathogenic SHQ1 variants result in disruptions to neuronal development and the dopaminergic pathway
Background
Compound heterozygous variants of SHQ1, an assembly factor of H/ACA ribonucleoproteins (RNPs) involved in critical biological pathways, have been identified in patients with developmental delay, dystonia, epilepsy, and microcephaly. We investigated the role of SHQ1 in brain development and movement disorders.
Methods
SHQ1 expression was knocked down using short-hairpin RNA (shRNA) to investigate its effects on neurons. Shq1 shRNA and cDNA of WT and mutant SHQ1 were also introduced into neural progenitors in the embryonic mouse cortex through in utero electroporation. Co-immunoprecipitation was performed to investigate the interaction between SHQ1 and DKC1, a core protein of H/ACA RNPs.
Results
We found that SHQ1 was highly expressed in the developing mouse cortex. SHQ1 knockdown impaired the migration and neurite morphology of cortical neurons during brain development. Additionally, SHQ1 knockdown impaired neurite growth and sensitivity to glutamate toxicity in vitro. There was also increased dopaminergic function upon SHQ1 knockdown, which may underlie the increased glutamate toxicity of the cells. Most SHQ1 variants attenuated their binding ability toward DKC1, implying SHQ1 variants may influence brain development by disrupting the assembly and biogenesis of H/ACA RNPs.
Conclusions
SHQ1 plays an essential role in brain development and dopaminergic function by upregulating dopaminergic pathways and regulating the behaviors of neural progenitors and their neuronal progeny, potentially leading to dystonia and developmental delay in patients. Our study provides insights into the functions of SHQ1 in neuronal development and dopaminergic function, providing a possible pathogenic mechanism for H/ACA RNPs-related disorders.
期刊介绍:
Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.