Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein functio...Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein function or structure,understanding their genetic basis is crucial for accurate diagnosis and targeted therapies.To investigate the underlying pathogenesis of these conditions,researchers often use non-mammalian model organisms,such as Drosophila(fruit flies),which is valued for their genetic manipulability,cost-efficiency,and preservation of genes and biological functions across evolutionary time.Genetic tools available in Drosophila,including CRISPR-Cas9,offer a means to manipulate gene expression,allowing for a deep exploration of the genetic underpinnings of rare neurological diseases.Drosophila boasts a versatile genetic toolkit,rapid generation turnover,and ease of large-scale experimentation,making it an invaluable resource for identifying potential drug candidates.Researchers can expose flies carrying disease-associated mutations to various compounds,rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and,ultimately,clinical trials.In this comprehensive review,we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis,pathophysiology,and potential therapeutic implications.We discuss rare diseases associated with both neuron-expressed and glial-expressed genes.Specific cases include mutations in CDK19 resulting in epilepsy and developmental delay,mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay,and mutations in IRF2BPL causing seizures,a neurodevelopmental disorder with regression,loss of speech,and abnormal movements.And we explore mutations in EMC1 related to cerebellar atrophy,visual impairment,psychomotor retardation,and gain-of-function mutations in ACOX1 causing Mitchell syndrome.Loss-of-function mutations in ACOX1 result in ACOX1 deficiency,characterized by very-long-chain fatty acid accumulation and glial degeneration.Notably,this review highlights how modeling these diseases in Drosophila has provided valuable insights into their pathophysiology,offering a platform for the rapid identification of potential therapeutic interventions.Rare neurological diseases involve a wide range of expression systems,and sometimes common phenotypes can be found among different genes that cause abnormalities in neurons or glia.Furthermore,mutations within the same gene may result in varying functional outcomes,such as complete loss of function,partial loss of function,or gain-of-function mutations.The phenotypes observed in patients can differ significantly,underscoring the complexity of these conditions.In conclusion,Drosophila represents an indispensable and cost-effective tool for investigating rare neurological diseases.By facilitating the modeling of these conditions,Drosophila contributes to a deeper understanding of their genetic basis,pathophysiology,and potential therapies.This approach accelerates the discovery of promising drug candidates,ultimately benefiting patients affected by these complex and understudied diseases.展开更多
超长链脂肪酸(very long chain fatty acids,VLCFAs)在生物体中具有广泛的生理功能,它们参与种子甘油酯、生物膜膜脂及鞘脂的合成,并为角质层蜡质的生物合成提供前体物质。角质层是覆盖在植物地上部分最表层的保护层,由角质和蜡质组成,...超长链脂肪酸(very long chain fatty acids,VLCFAs)在生物体中具有广泛的生理功能,它们参与种子甘油酯、生物膜膜脂及鞘脂的合成,并为角质层蜡质的生物合成提供前体物质。角质层是覆盖在植物地上部分最表层的保护层,由角质和蜡质组成,其中蜡质又分为角质层表皮蜡和内部蜡,在植物生长发育、适应外界环境方面起重要作用。VLCFAs的合成由脂肪酰-CoA延长酶催化,该酶是由β-酮脂酰-CoA合酶、β-酮脂酰-CoA还原酶、β-羟脂酰-CoA脱水酶和反式烯脂酰-CoA还原酶组成的多酶体系。合成后的VLCFAs通过脱羰基与酰基还原作用进入角质层蜡质合成途径,形成各种蜡质组分。文章就VLCFAs及角质层蜡质合成代谢途径中相关酶基因研究进展方面做了综述,并对植物蜡质基因研究中存在的问题提出一些看法。展开更多
超长链脂肪酸延伸酶(elongase of verylong chain fatty acids,ELOVL)家族是哺乳动物中一类编码超长链脂肪酸(very long chain fatty acids,VLCFA)延伸酶的基因家族。该家族有7个成员:ELOVL1～7。各个成员编码的蛋白质参与不同长度脂肪...超长链脂肪酸延伸酶(elongase of verylong chain fatty acids,ELOVL)家族是哺乳动物中一类编码超长链脂肪酸(very long chain fatty acids,VLCFA)延伸酶的基因家族。该家族有7个成员:ELOVL1～7。各个成员编码的蛋白质参与不同长度脂肪酸链的延长,对脂肪酸的代谢进行调控,进而发挥其生物学功能。本文就该家族成员的结构、生物学功能及表达调控进行综述。展开更多
目的报道1例以双下肢无力、走路不稳为主要表现的肾上腺脊髓神经病(adrenomyeloneuropathy,AMN)患者的诊断和洛伦佐油治疗半年的随访经历,并结合文献讨论AMN诊断及治疗。方法纳入应急总医院2022年9月明确诊断的1例AMN患者,分析患者外周...目的报道1例以双下肢无力、走路不稳为主要表现的肾上腺脊髓神经病(adrenomyeloneuropathy,AMN)患者的诊断和洛伦佐油治疗半年的随访经历,并结合文献讨论AMN诊断及治疗。方法纳入应急总医院2022年9月明确诊断的1例AMN患者,分析患者外周静脉血促肾上腺皮质激素(adrenocorticotropic hormone,ACTH)、血皮质醇、血清极长链脂肪酸(very long chain fatty acids,VLCFAs)水平、头颅MRI及AMN相关基因,并观察患者服用洛伦佐油(Lorenzo's Oil)20 mL/d治疗半年后病情变化情况。结果患者治疗前实验室检查结果提示肾上腺皮质功能减退(ACTH水平明显升高,血皮质醇水平明显减低),二十四烷酸(C24:0)、二十六烷酸(C26:0)水平以及C24:0/C22:0、C26:0/C22:0比值等VLCFAs指标增高,脑MRI提示双侧内囊锥体束高信号、大脑脚锥体束稍高信号,高通量全外显子基因测序显示ATP结合超家族D亚组膜1(ATP binding cassette subfamily D member 1,ABCD1)基因(NM-000033)外显子7发生c.1768C>T半合子变异,导致第590位氨基酸由丝氨酸变异为亮氨酸,为错义突变。使用洛伦佐油20 mL/d治疗半年后,临床症状部分好转,复查ACTH、血皮质醇水平等激素指标有所下降,C26:0水平及C24:0/C22:0及C26:0/C22:0比值等VLCFAs指标也均有明显下降。结论以双下肢无力,走路不稳为主要表现的患者,应考虑AMN可能,完善血清极长链脂肪酸和ABCD1基因检测以明确诊断,早诊早治。展开更多
The reduced diameter of skeletal myofibres is a hallmark of several congenital myopathies,yet the underlying cellular and molecular mechanisms remain elusive.In this study,we investigate the role of HACD1/PTPLA,which ...The reduced diameter of skeletal myofibres is a hallmark of several congenital myopathies,yet the underlying cellular and molecular mechanisms remain elusive.In this study,we investigate the role of HACD1/PTPLA,which is involved in the elongation of the very long chain fatty acids,in muscle fibre formation.In humans and dogs,HACD1 deficiency leads to a congenital myopathy with fibre size disproportion associated with a generalized muscleweakness.Throughanalysis of HACD1-deficient Labradors,Hacd1-knockout mice,and Hacd1-deficient myoblasts,we provide evidence that HACD1 promotes myoblast fusion during muscle development and regeneration.We further demonstrate that in normal differentiating myoblasts,expression of the catalytically active HACD1 isoform,which is encoded by a muscle-enriched splice variant,yields decreased lysophosphatidylcholine content,a potent inhibitor of myoblast fusion,and increased concentrations of≥C18 and monounsaturated fatty acids of phospholipids.These lipid modifications correlate with a reduction in plasma membrane rigidity.In conclusion,we propose that fusion impairment constitutes a novel,non-exclusive pathological mechanism operating in congenital myopathies and reveal that HACD1 is a key regulator of a lipid-dependent muscle fibre growth mechanism.展开更多
Peroxisomal disorders(PDs)are a heterogenous group of diseases caused by defects in peroxisome biogenesis or functions.Xlinked adrenoleukodystrophy is the most prevalent form of PDs and results from mutations in the A...Peroxisomal disorders(PDs)are a heterogenous group of diseases caused by defects in peroxisome biogenesis or functions.Xlinked adrenoleukodystrophy is the most prevalent form of PDs and results from mutations in the ABCD1 gene,which encodes a transporter mediating the uptake of very long-chain fatty acids(VLCFAs).The curative approaches for PDs are very limited.Here,we investigated whether cholesterol accumulation in the lysosomes is a biochemical feature shared by a broad spectrum of PDs.We individually knocked down fifteen PD-associated genes in cultured cells and found ten induced cholesterol accumulation in the lysosome.2-Hydroxypropyl-β-cyclodextrin(HPCD)effectively alleviated the cholesterol accumulation phenotype in PD-mimicking cells through reducing intracellular cholesterol content as well as promoting cholesterol redistribution to other cellular membranes.In ABCD1 knockdown cells,HPCD treatment lowered reactive oxygen species and VLCFA to normal levels.In Abcd1 knockout mice,HPCD injections reduced cholesterol and VLCFA sequestration in the brain and adrenal cortex.The plasma levels of adrenocortical hormones were increased and the behavioral abnormalities were greatly ameliorated upon HPCD administration.Together,our results suggest that defective cholesterol transport underlies most,if not all,PDs,and that HPCD can serve as a novel and effective strategy for the treatment of PDs.展开更多
基金supported by Warren Alpert Foundation and Houston Methodist Academic Institute Laboratory Operating Fund(to HLC).
文摘Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein function or structure,understanding their genetic basis is crucial for accurate diagnosis and targeted therapies.To investigate the underlying pathogenesis of these conditions,researchers often use non-mammalian model organisms,such as Drosophila(fruit flies),which is valued for their genetic manipulability,cost-efficiency,and preservation of genes and biological functions across evolutionary time.Genetic tools available in Drosophila,including CRISPR-Cas9,offer a means to manipulate gene expression,allowing for a deep exploration of the genetic underpinnings of rare neurological diseases.Drosophila boasts a versatile genetic toolkit,rapid generation turnover,and ease of large-scale experimentation,making it an invaluable resource for identifying potential drug candidates.Researchers can expose flies carrying disease-associated mutations to various compounds,rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and,ultimately,clinical trials.In this comprehensive review,we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis,pathophysiology,and potential therapeutic implications.We discuss rare diseases associated with both neuron-expressed and glial-expressed genes.Specific cases include mutations in CDK19 resulting in epilepsy and developmental delay,mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay,and mutations in IRF2BPL causing seizures,a neurodevelopmental disorder with regression,loss of speech,and abnormal movements.And we explore mutations in EMC1 related to cerebellar atrophy,visual impairment,psychomotor retardation,and gain-of-function mutations in ACOX1 causing Mitchell syndrome.Loss-of-function mutations in ACOX1 result in ACOX1 deficiency,characterized by very-long-chain fatty acid accumulation and glial degeneration.Notably,this review highlights how modeling these diseases in Drosophila has provided valuable insights into their pathophysiology,offering a platform for the rapid identification of potential therapeutic interventions.Rare neurological diseases involve a wide range of expression systems,and sometimes common phenotypes can be found among different genes that cause abnormalities in neurons or glia.Furthermore,mutations within the same gene may result in varying functional outcomes,such as complete loss of function,partial loss of function,or gain-of-function mutations.The phenotypes observed in patients can differ significantly,underscoring the complexity of these conditions.In conclusion,Drosophila represents an indispensable and cost-effective tool for investigating rare neurological diseases.By facilitating the modeling of these conditions,Drosophila contributes to a deeper understanding of their genetic basis,pathophysiology,and potential therapies.This approach accelerates the discovery of promising drug candidates,ultimately benefiting patients affected by these complex and understudied diseases.
文摘超长链脂肪酸(very long chain fatty acids,VLCFAs)在生物体中具有广泛的生理功能,它们参与种子甘油酯、生物膜膜脂及鞘脂的合成,并为角质层蜡质的生物合成提供前体物质。角质层是覆盖在植物地上部分最表层的保护层,由角质和蜡质组成,其中蜡质又分为角质层表皮蜡和内部蜡,在植物生长发育、适应外界环境方面起重要作用。VLCFAs的合成由脂肪酰-CoA延长酶催化,该酶是由β-酮脂酰-CoA合酶、β-酮脂酰-CoA还原酶、β-羟脂酰-CoA脱水酶和反式烯脂酰-CoA还原酶组成的多酶体系。合成后的VLCFAs通过脱羰基与酰基还原作用进入角质层蜡质合成途径,形成各种蜡质组分。文章就VLCFAs及角质层蜡质合成代谢途径中相关酶基因研究进展方面做了综述,并对植物蜡质基因研究中存在的问题提出一些看法。
文摘超长链脂肪酸延伸酶(elongase of verylong chain fatty acids,ELOVL)家族是哺乳动物中一类编码超长链脂肪酸(very long chain fatty acids,VLCFA)延伸酶的基因家族。该家族有7个成员:ELOVL1～7。各个成员编码的蛋白质参与不同长度脂肪酸链的延长,对脂肪酸的代谢进行调控,进而发挥其生物学功能。本文就该家族成员的结构、生物学功能及表达调控进行综述。
文摘目的报道1例以双下肢无力、走路不稳为主要表现的肾上腺脊髓神经病(adrenomyeloneuropathy,AMN)患者的诊断和洛伦佐油治疗半年的随访经历,并结合文献讨论AMN诊断及治疗。方法纳入应急总医院2022年9月明确诊断的1例AMN患者,分析患者外周静脉血促肾上腺皮质激素(adrenocorticotropic hormone,ACTH)、血皮质醇、血清极长链脂肪酸(very long chain fatty acids,VLCFAs)水平、头颅MRI及AMN相关基因,并观察患者服用洛伦佐油(Lorenzo's Oil)20 mL/d治疗半年后病情变化情况。结果患者治疗前实验室检查结果提示肾上腺皮质功能减退(ACTH水平明显升高,血皮质醇水平明显减低),二十四烷酸(C24:0)、二十六烷酸(C26:0)水平以及C24:0/C22:0、C26:0/C22:0比值等VLCFAs指标增高,脑MRI提示双侧内囊锥体束高信号、大脑脚锥体束稍高信号,高通量全外显子基因测序显示ATP结合超家族D亚组膜1(ATP binding cassette subfamily D member 1,ABCD1)基因(NM-000033)外显子7发生c.1768C>T半合子变异,导致第590位氨基酸由丝氨酸变异为亮氨酸,为错义突变。使用洛伦佐油20 mL/d治疗半年后,临床症状部分好转,复查ACTH、血皮质醇水平等激素指标有所下降,C26:0水平及C24:0/C22:0及C26:0/C22:0比值等VLCFAs指标也均有明显下降。结论以双下肢无力,走路不稳为主要表现的患者,应考虑AMN可能,完善血清极长链脂肪酸和ABCD1基因检测以明确诊断,早诊早治。
基金This work was supported by the Agence Nationale de la Recherche(ANR-12-JSV1-0005)the Association Franc¸aise contre les Myopathies(14577,15882,and 16143)+4 种基金the CNM Project(www.labradorcnm.com)the Alliance program(22866ZM)the Myotubular Trust and Grants-in-Aid for Scientific Research(B)to A.K.from Japan Society for the Promotion of Science(23370057)J.B.was supported by the French Ministry of Research and Technologies and the Universite´Paris 6(Paris)V.G.,A.P.,and A.R.were supported by the ANR,N.B-G.and I.B.were supported by the AFM,and G.W.was supported by the BBSRC CASE and the Myotubular Trust.
文摘The reduced diameter of skeletal myofibres is a hallmark of several congenital myopathies,yet the underlying cellular and molecular mechanisms remain elusive.In this study,we investigate the role of HACD1/PTPLA,which is involved in the elongation of the very long chain fatty acids,in muscle fibre formation.In humans and dogs,HACD1 deficiency leads to a congenital myopathy with fibre size disproportion associated with a generalized muscleweakness.Throughanalysis of HACD1-deficient Labradors,Hacd1-knockout mice,and Hacd1-deficient myoblasts,we provide evidence that HACD1 promotes myoblast fusion during muscle development and regeneration.We further demonstrate that in normal differentiating myoblasts,expression of the catalytically active HACD1 isoform,which is encoded by a muscle-enriched splice variant,yields decreased lysophosphatidylcholine content,a potent inhibitor of myoblast fusion,and increased concentrations of≥C18 and monounsaturated fatty acids of phospholipids.These lipid modifications correlate with a reduction in plasma membrane rigidity.In conclusion,we propose that fusion impairment constitutes a novel,non-exclusive pathological mechanism operating in congenital myopathies and reveal that HACD1 is a key regulator of a lipid-dependent muscle fibre growth mechanism.
基金supported by the China Postdoctoral Science Foundation Grant(2021M692478)the Ministry of Science and Technology of China(2018YFA0800703)+2 种基金the National Natural Science Foundation of China(32293203,31771568)111 Project of Ministry of Education of China(B16036)the support from the Tencent Foundation through the XPLORER PRIZE。
文摘Peroxisomal disorders(PDs)are a heterogenous group of diseases caused by defects in peroxisome biogenesis or functions.Xlinked adrenoleukodystrophy is the most prevalent form of PDs and results from mutations in the ABCD1 gene,which encodes a transporter mediating the uptake of very long-chain fatty acids(VLCFAs).The curative approaches for PDs are very limited.Here,we investigated whether cholesterol accumulation in the lysosomes is a biochemical feature shared by a broad spectrum of PDs.We individually knocked down fifteen PD-associated genes in cultured cells and found ten induced cholesterol accumulation in the lysosome.2-Hydroxypropyl-β-cyclodextrin(HPCD)effectively alleviated the cholesterol accumulation phenotype in PD-mimicking cells through reducing intracellular cholesterol content as well as promoting cholesterol redistribution to other cellular membranes.In ABCD1 knockdown cells,HPCD treatment lowered reactive oxygen species and VLCFA to normal levels.In Abcd1 knockout mice,HPCD injections reduced cholesterol and VLCFA sequestration in the brain and adrenal cortex.The plasma levels of adrenocortical hormones were increased and the behavioral abnormalities were greatly ameliorated upon HPCD administration.Together,our results suggest that defective cholesterol transport underlies most,if not all,PDs,and that HPCD can serve as a novel and effective strategy for the treatment of PDs.
