Parkinson’s disease is the second most common neurodegenerative disorder.ATPase H+transporting V0 subunit A1(ATP6V0A1)is a component of vacuolar H+-ATPase(V-ATPase),an ATP-dependent proton pump.Our previous research ...Parkinson’s disease is the second most common neurodegenerative disorder.ATPase H+transporting V0 subunit A1(ATP6V0A1)is a component of vacuolar H+-ATPase(V-ATPase),an ATP-dependent proton pump.Our previous research identified an association between the ATP6V0A1 rs601999 variant and Parkinson’s disease;however,the underlying mechanisms of ATP6V0A1 in Parkinson’s disease remain elusive.In this study,we generated ATP6V0A1 knockdown and overexpression models and then examined the degeneration of dopaminergic neurons,lysosomal function,and the autophagy-lysosomal pathway using immunohistochemistry,western blotting,and transmission electron microscopy.We found that ATP6V0A1 protected against lysosomal dysfunction,regulated autophagic flux,and decreased phosphorylatedα-synuclein levels in vitro.In vivo,ATP6V0A1 reduced levels ofα-synuclein and phosphorylatedα-synuclein proteins,mitigated degeneration of dopaminergic neurons,and improved motor dysfunction.Collectively,these findings show that ATP6V0A1 plays a protective role in Parkinson’s disease by modulating the autophagy-lysosomal pathway.A correlation between ATP6V0A1 and Parkinson’s disease susceptibility may serve as a biomarker for Parkinson’s disease,while the protective effects of ATP6V0A1 could represent a potential therapeutic target for the disease.展开更多
发育性和癫痫性脑病93(Developmental and epileptic encephalopathy 93,DEE93)(MIM:618012)是一种常染色体显性遗传神经系统疾病,主要特点为精神运动发育迟缓、早发难治性癫痫和智力低下等,且与ATP6V1A基因变异有关^([1])。DEE93临床...发育性和癫痫性脑病93(Developmental and epileptic encephalopathy 93,DEE93)(MIM:618012)是一种常染色体显性遗传神经系统疾病,主要特点为精神运动发育迟缓、早发难治性癫痫和智力低下等,且与ATP6V1A基因变异有关^([1])。DEE93临床表现差异大,病情轻重不一,重者可因快速进展的早期致命性脑病而死亡,轻者仅表现为轻度至中度智力障碍,伴或不伴癫痫发作^([2-3])。ATP6V1A基因(MIM#607027)染色体位置为3q13.3,包含15个外显子,编码617个氨基酸,是组成ATP酶(V-ATPase)的一个亚基,参与介导真核细胞内的质子运输过程和细胞器的酸化。本文报告了1例全外显子测序发现ATP6V1A基因杂合致病性变异c.937G>C:p.Ala313Pro的婴儿,描述了其临床表现并复习相关文献内容,扩展了ATP6V1A基因突变相关DEE93的临床特征和遗传谱,为该病的诊断、治疗和遗传咨询提供参考。展开更多
BACKGROUND Depression is a disease with a significant global social burden.Single nucleotide polymorphisms(SNPs)are correlated with the development of depression.This study investigates the relationship between polymo...BACKGROUND Depression is a disease with a significant global social burden.Single nucleotide polymorphisms(SNPs)are correlated with the development of depression.This study investigates the relationship between polymorphisms in the GPHN and ATP6V1D gene promoter regions and susceptibility to depression in the Chinese population.AIM To provide new insights into identifying SNPs for predicting depression in the Chinese population.METHODS We conducted a case-control study involving 555 individuals with depression and 509 healthy controls.GPHN rs8020095 and ATP6V1D rs3759755,rs10144417,rs2031564,and rs8016024 in the promoter region were genotyped using nextgeneration sequencing.Dual luciferase reporter genes were employed to assess the transcriptional activity of promoter regions for each SNP genotype,with transcription factors binding to each site predicted using the JASPAR database.RESULTS Compared to healthy controls,the ATP6V1D promoter rs10144417 AG genotype (P = 0.015), rs3759755 AC/CC genotype (P = 0.036), and GPHN gene rs8020095 GA and AA genotypes (GA: P =0.028, GG: P = 0.025) were significantly associated with a lower prevalence of depression. Linked disequilibria werepresent in five SNPs, with the AGATA haplotype frequency in patients significantly lower than in healthy subjects(P = 0.023). Luciferase activity of the rs3759755-A recombinant plasmid was significantly higher than that of thers3759755-C recombinant plasmid (P = 0.026), and the rs8020095-A recombinant plasmid activity was significantlyhigher than that of the rs8020095-G recombinant plasmid (P = 0.001). Transcription factors orthodenticle homeobox2, orthodenticle homeobox 1, forkhead box L1, NK homeobox 3-1, and nuclear factor, interleukin 3 regulateddemonstrated binding affinity with rs3759755A > C and rs8020095A > G.CONCLUSIONThis study demonstrates that SNPs (rs3759755 and rs10144417) in the promoter region of the ATP6V1D and SNP(rs8020095) of GPHN are indeed associated with susceptibility to depression.展开更多
基金supported by the Youth Program of the National Natural Science Foundation of China,Nos.81901282(to XC),82101326(to WG),81870992(to PX),and 81870856the Guangdong Basic and Applied Basic Research Foundation of the Science Foundation,Nos.2024A1515012919(to XC)and 2019A1515011189(to XC)+5 种基金the Central Government Guiding Local Science and Technology Development Projects,No.ZYYD2022C17(to PX)the Key Project of the Guangzhou Health Commission,No.2019-ZD-09(to PX)the Basic and Applied Basic Research of the City and School Jointly Funded Projects,No.20220102397(to QL)the Guangdong College Students Innovation and Entrepreneurship Training Program,No.S202310570017(to WY)the Science and Technology Planning Project of Guangzhou,Nos.2023B03J0631(to PX),2024A03J1152(to XC),and 202102010010(to PX)the Basic Research Program of the Guangzhou Science and Technology Bureau Jointly-funded Dengfeng Hospital Project,No.20232031(to XC).
文摘Parkinson’s disease is the second most common neurodegenerative disorder.ATPase H+transporting V0 subunit A1(ATP6V0A1)is a component of vacuolar H+-ATPase(V-ATPase),an ATP-dependent proton pump.Our previous research identified an association between the ATP6V0A1 rs601999 variant and Parkinson’s disease;however,the underlying mechanisms of ATP6V0A1 in Parkinson’s disease remain elusive.In this study,we generated ATP6V0A1 knockdown and overexpression models and then examined the degeneration of dopaminergic neurons,lysosomal function,and the autophagy-lysosomal pathway using immunohistochemistry,western blotting,and transmission electron microscopy.We found that ATP6V0A1 protected against lysosomal dysfunction,regulated autophagic flux,and decreased phosphorylatedα-synuclein levels in vitro.In vivo,ATP6V0A1 reduced levels ofα-synuclein and phosphorylatedα-synuclein proteins,mitigated degeneration of dopaminergic neurons,and improved motor dysfunction.Collectively,these findings show that ATP6V0A1 plays a protective role in Parkinson’s disease by modulating the autophagy-lysosomal pathway.A correlation between ATP6V0A1 and Parkinson’s disease susceptibility may serve as a biomarker for Parkinson’s disease,while the protective effects of ATP6V0A1 could represent a potential therapeutic target for the disease.
文摘发育性和癫痫性脑病93(Developmental and epileptic encephalopathy 93,DEE93)(MIM:618012)是一种常染色体显性遗传神经系统疾病,主要特点为精神运动发育迟缓、早发难治性癫痫和智力低下等,且与ATP6V1A基因变异有关^([1])。DEE93临床表现差异大,病情轻重不一,重者可因快速进展的早期致命性脑病而死亡,轻者仅表现为轻度至中度智力障碍,伴或不伴癫痫发作^([2-3])。ATP6V1A基因(MIM#607027)染色体位置为3q13.3,包含15个外显子,编码617个氨基酸,是组成ATP酶(V-ATPase)的一个亚基,参与介导真核细胞内的质子运输过程和细胞器的酸化。本文报告了1例全外显子测序发现ATP6V1A基因杂合致病性变异c.937G>C:p.Ala313Pro的婴儿,描述了其临床表现并复习相关文献内容,扩展了ATP6V1A基因突变相关DEE93的临床特征和遗传谱,为该病的诊断、治疗和遗传咨询提供参考。
基金Supported by the Natural Science Foundation of Sichuan,China,No.2022NSFSC0778Research Project Foundation of Sichuan Applied Psychology Research Center,No.CSXL-24202+1 种基金Foundation of Sichuan Clinical Research Center for Geriatrics,No.24LHLNYX1-04 and No.24LHLNYX1-06and the Key Laboratory Foundation for Development and Regeneration of Sichuan Province,No.24LHFYSZ1-25.
文摘BACKGROUND Depression is a disease with a significant global social burden.Single nucleotide polymorphisms(SNPs)are correlated with the development of depression.This study investigates the relationship between polymorphisms in the GPHN and ATP6V1D gene promoter regions and susceptibility to depression in the Chinese population.AIM To provide new insights into identifying SNPs for predicting depression in the Chinese population.METHODS We conducted a case-control study involving 555 individuals with depression and 509 healthy controls.GPHN rs8020095 and ATP6V1D rs3759755,rs10144417,rs2031564,and rs8016024 in the promoter region were genotyped using nextgeneration sequencing.Dual luciferase reporter genes were employed to assess the transcriptional activity of promoter regions for each SNP genotype,with transcription factors binding to each site predicted using the JASPAR database.RESULTS Compared to healthy controls,the ATP6V1D promoter rs10144417 AG genotype (P = 0.015), rs3759755 AC/CC genotype (P = 0.036), and GPHN gene rs8020095 GA and AA genotypes (GA: P =0.028, GG: P = 0.025) were significantly associated with a lower prevalence of depression. Linked disequilibria werepresent in five SNPs, with the AGATA haplotype frequency in patients significantly lower than in healthy subjects(P = 0.023). Luciferase activity of the rs3759755-A recombinant plasmid was significantly higher than that of thers3759755-C recombinant plasmid (P = 0.026), and the rs8020095-A recombinant plasmid activity was significantlyhigher than that of the rs8020095-G recombinant plasmid (P = 0.001). Transcription factors orthodenticle homeobox2, orthodenticle homeobox 1, forkhead box L1, NK homeobox 3-1, and nuclear factor, interleukin 3 regulateddemonstrated binding affinity with rs3759755A > C and rs8020095A > G.CONCLUSIONThis study demonstrates that SNPs (rs3759755 and rs10144417) in the promoter region of the ATP6V1D and SNP(rs8020095) of GPHN are indeed associated with susceptibility to depression.
