神经递质......一切都与沟通有关!

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Journal of Inherited Metabolic Disease Pub Date : 2024-05-15 DOI:10.1002/jimd.12748
Thomas Opladen, Mariarita Bertoldi
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The umbrella term “neurotransmitter” encompasses different types of chemical substances involved in synaptic transmission from cell to cell within the central and peripheral nervous system. Neurotransmitters can be grouped according to their chemical structure into amino acid transmitters (glycine, glutamate and γ-aminobutyric acid (GABA)), monoamines/biogenic amine transmitters, (with the subgroup of catecholamines norepinephrine, epinephrine, and dopamine as well as serotonin), and neuropeptides. Atypical neurotransmitters, as the purinergic neurotransmitters adenosine and adenosine triphosphate (ATP), endogenous cannabinoids and opioids, diffusible gases like nitric oxide (NO) or carbon monoxide (CO) and families of neurotrophic factors and cytokines have either unusual chemical properties or are less extensively studied and understood. 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This special issue of the <i>Journal of Inherited Metabolic Disease</i> discusses conference highlights from all three perspectives.</p><p>The patient organizations were active contributors to the discussion and, led by Lil' Brave One and SSADH-Defizit e.V., identified unique challenges associated with the diagnostic odyssey for rare neurotransmitter diseases, assessed the factors contributing to diagnostic delay, and proposed strategies to improve the diagnostic process.<span><sup>2</sup></span> They further recognized four main gaps between patients, clinicians and scientists.<span><sup>3</sup></span></p><p>Several scientists and clinicians contributed original research and review articles on the topic of neurotransmitter-related disorders. The review focused on a metabolomic perspective involving succinic semialdehyde (SSADH) deficiency.<span><sup>4</sup></span> Within the manuscripts on clinical research Yildiz et al. added hyperprolactinaemia-related findings such as levodopa-refractory hyperprolactinaemia, or abnormal pituitary findings to the current knowledge of the phenotypic spectrum of inherited disorders of biogenic amine metabolism.<span><sup>5</sup></span> Julia-Palacios broadened the phenotypic spectrum of SSADH deficieny, expanded the number of pathogenic variants and emphasizes a reliable application of in silico approaches.<span><sup>6</sup></span></p><p>Another focus was new treatment approaches. Roubertie et al. outlined the standards and requirements for the preparation, management and follow-up of patients with AADC deficiency who undergo gene therapy,<span><sup>7</sup></span> while Lee et al. summarized the current state of gene replacement therapies in SSADH deficieny.<span><sup>8</sup></span> An outlook on new therapy options is also provided by Noguero<span><sup>9</sup></span> with reference to the stabilization of tyrosine hydroxylase (TH) and tyrosine hydroxylase deficiency phenotypes by tetrahydrobiopterin, while the development of precision therapies for rare inborn errors of metabolism, with special attention on drug repurposing and cell culture models is summarized by Didiasova et al.<span><sup>10</sup></span></p><p>An extensive characterization of pathogenic variants in TH cells including expression, localization and stability together with their physical interaction with GTP cyclohydrolase 1<span><sup>11</sup></span> provides the basis for identification of novel molecules and other approaches to treat the disorders dependent on these proteins. 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This special issue of the <i>Journal of Inherited Metabolic Disease</i> discusses conference highlights from all three perspectives.</p><p>The patient organizations were active contributors to the discussion and, led by Lil' Brave One and SSADH-Defizit e.V., identified unique challenges associated with the diagnostic odyssey for rare neurotransmitter diseases, assessed the factors contributing to diagnostic delay, and proposed strategies to improve the diagnostic process.<span><sup>2</sup></span> They further recognized four main gaps between patients, clinicians and scientists.<span><sup>3</sup></span></p><p>Several scientists and clinicians contributed original research and review articles on the topic of neurotransmitter-related disorders. 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引用次数: 0

摘要

大脑功能取决于神经元在回路中的连接,这些回路的规模小到局部神经元群,大到远距离投射。神经元可以在一个以上的回路中发挥功能,并通过超过 100 万亿个突触与成千上万个其他神经元进行交流。1 在经典的突触组织中,突触前发送神经元将化学物质("神经递质")从储存在轴突中的囊泡释放到突触间隙中。在突触后接收神经元处,神经递质与特定受体结合,这种结合改变了突触后神经元的电活动,进而导致神经元间的进一步交流。神经递质 "这一总称包括中枢神经系统和周围神经系统中细胞与细胞之间突触传递所涉及的不同类型的化学物质。神经递质可根据其化学结构分为氨基酸递质(甘氨酸、谷氨酸和γ-氨基丁酸(GABA))、单胺/生物胺递质(包括儿茶酚胺子类去甲肾上腺素、肾上腺素和多巴胺以及血清素)和神经肽。非典型神经递质,如嘌呤能神经递质腺苷和三磷酸腺苷(ATP)、内源性大麻素和阿片类物质、一氧化氮(NO)或一氧化碳(CO)等可扩散气体以及神经营养因子和细胞因子家族,要么具有不寻常的化学特性,要么研究和了解较少。交流也是 "罕见神经递质相关疾病--从研究到治疗(RNTD-R2T)"会议的主要目标,会议在塞尔维亚贝尔格莱德市举行,来自 24 个国家的 184 名与会者参加了会议。在欧洲罕见疾病联合计划(EJPRD)的资助下,为了促进所有利益相关者的参与和交流,会议汇集了经验丰富的临床科学家、基础研究人员、早期职业研究人员和患者权益组织。本期《遗传代谢病杂志》特刊从这三个角度讨论了会议的亮点。患者组织积极参与了讨论,并在 Lil' Brave One 和 SSADH-Defizit e.V. 的领导下,确定了与诊断和治疗相关的独特挑战、2 他们进一步认识到了患者、临床医生和科学家之间存在的四大差距。3 一些科学家和临床医生就神经递质相关疾病这一主题发表了原创研究和综述文章。Yildiz 等人在有关临床研究的手稿中增加了与高催乳素血症相关的研究结果,如左旋多巴难治性高催乳素血症,或垂体异常的研究结果,使人们对生物胺代谢遗传性疾病的表型谱有了更多的了解。Julia-Palacios 拓宽了 SSADH 缺乏症的表型谱,增加了致病变体的数量,并强调要可靠地应用硅学方法。Roubertie 等人概述了接受基因治疗的 AADC 缺乏症患者的准备、管理和随访的标准和要求,7 Lee 等人总结了 SSADH 缺乏症基因替代疗法的现状。Noguero9 也对新疗法进行了展望,提到了四氢生物蝶呤对酪氨酸羟化酶(TH)和酪氨酸羟化酶缺乏症表型的稳定作用,而 Didiasova 等人10 则总结了罕见先天性代谢异常精准疗法的发展情况,特别关注了药物再利用和细胞培养模型。对 TH 细胞中致病变体的表达、定位和稳定性以及它们与 GTP 环醇酶 111 的物理相互作用进行了广泛的表征,为确定治疗依赖于这些蛋白的疾病的新型分子和其他方法奠定了基础。13 值得注意的是,作为 RNTD-R2T 会议的一项成果,在维罗纳(2023 年 9 月)举办了神经递质紊乱青年科学家论坛,专门面向新一代临床医生和科学家,他们的临床和研究重点与先天性神经递质疾病相关。
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Neurotransmitters … it is all about communication!

Brain function depends on neuronal connections in circuits, which range in scale from small local neuronal groups to long-distance projections. Neurons can function in more than one circuit and communicate with thousands of other neurons through more than 100 trillion synapses.1 In the classical synaptic organization, a presynaptic transmitting neuron releases chemical substances (“neurotransmitters”) from vesicles stored in the axon into the synaptic cleft. At the postsynaptic receiving neuron, the neurotransmitter binds to specific receptors and the binding changes the electrical activity of the postsynaptic neuron, which in turn leads to further interneuron communication. The umbrella term “neurotransmitter” encompasses different types of chemical substances involved in synaptic transmission from cell to cell within the central and peripheral nervous system. Neurotransmitters can be grouped according to their chemical structure into amino acid transmitters (glycine, glutamate and γ-aminobutyric acid (GABA)), monoamines/biogenic amine transmitters, (with the subgroup of catecholamines norepinephrine, epinephrine, and dopamine as well as serotonin), and neuropeptides. Atypical neurotransmitters, as the purinergic neurotransmitters adenosine and adenosine triphosphate (ATP), endogenous cannabinoids and opioids, diffusible gases like nitric oxide (NO) or carbon monoxide (CO) and families of neurotrophic factors and cytokines have either unusual chemical properties or are less extensively studied and understood. All neurotransmitters are essential for the unique and highly orchestrated process of synaptic communication.

Communication was also the main goal of the conference “Rare-neurotransmitter-related diseases—Research to treatment (RNTD-R2T)” which took place in the city of Belgrade, Serbia, with 184 participants from 24 countries. With funding from the European Joint Programme Rare Diseases (EJPRD) and with the aim of fostering involvement of and exchange between all stakeholders, the conference brought together experienced clinical scientists and basic researchers with Early Career Researchers and patient advocacy organizations. This special issue of the Journal of Inherited Metabolic Disease discusses conference highlights from all three perspectives.

The patient organizations were active contributors to the discussion and, led by Lil' Brave One and SSADH-Defizit e.V., identified unique challenges associated with the diagnostic odyssey for rare neurotransmitter diseases, assessed the factors contributing to diagnostic delay, and proposed strategies to improve the diagnostic process.2 They further recognized four main gaps between patients, clinicians and scientists.3

Several scientists and clinicians contributed original research and review articles on the topic of neurotransmitter-related disorders. The review focused on a metabolomic perspective involving succinic semialdehyde (SSADH) deficiency.4 Within the manuscripts on clinical research Yildiz et al. added hyperprolactinaemia-related findings such as levodopa-refractory hyperprolactinaemia, or abnormal pituitary findings to the current knowledge of the phenotypic spectrum of inherited disorders of biogenic amine metabolism.5 Julia-Palacios broadened the phenotypic spectrum of SSADH deficieny, expanded the number of pathogenic variants and emphasizes a reliable application of in silico approaches.6

Another focus was new treatment approaches. Roubertie et al. outlined the standards and requirements for the preparation, management and follow-up of patients with AADC deficiency who undergo gene therapy,7 while Lee et al. summarized the current state of gene replacement therapies in SSADH deficieny.8 An outlook on new therapy options is also provided by Noguero9 with reference to the stabilization of tyrosine hydroxylase (TH) and tyrosine hydroxylase deficiency phenotypes by tetrahydrobiopterin, while the development of precision therapies for rare inborn errors of metabolism, with special attention on drug repurposing and cell culture models is summarized by Didiasova et al.10

An extensive characterization of pathogenic variants in TH cells including expression, localization and stability together with their physical interaction with GTP cyclohydrolase 111 provides the basis for identification of novel molecules and other approaches to treat the disorders dependent on these proteins. The issue also reports the development of mouse models for monoamine neurotransmitter disorders12 and the metabolic characterization of neurogenetic disorders involving the glutamatergic neurotransmission.13

Notably, as a consequence of the RNTD-R2T Conference, a Young Scientist Forum on neurotransmitter disorders occurred in Verona (September 2023) dedicated to the new generation of clinicians and scientists, whose clinical and research focus is related to inborn neurotransmitter diseases. The scientific forum was coupled to training in communication with each other and patient advocacy groups, to transmit scientific messages clearly and efficiently.

Altogether, this special issue presents a wide collection of contributions on inherited neurotransmitter diseases, encompassing patient, clinical and basic science perspectives. It underlines the challenges, the latest developments and the innovations in therapies and highlights the importance for communication to inspire and foster future research and clinical studies.

HORIZON EUROPE Framework Programme, Grant/Award Number: 825575.

The authors do not have any conflicts of interest to declare.

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来源期刊
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease 医学-内分泌学与代谢
CiteScore
9.50
自引率
7.10%
发文量
117
审稿时长
4-8 weeks
期刊介绍: The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).
期刊最新文献
News from Valencia: JIMD themed issue on ureagenesis defects and allied disorders. The relation between dietary polysaccharide intake and urinary excretion of tetraglucoside. Nontargeted urine metabolomic analysis of acute intermittent porphyria reveals novel interactions between bile acids and heme metabolism: New promising biomarkers for the long-term management of patients. Exploring RNA therapeutics for urea cycle disorders. Therapeutic liver cell transplantation to treat murine PKU.
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