Dopamine Degradation Pathway and Alpha-synuclein Aggregation
多巴胺降解途径和 α-突触核蛋白聚集
基本信息
- 批准号:10002314
- 负责人:
- 金额:$ 37.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-25 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:3,4-Dihydroxyphenylacetic AcidAccountingAffectAldehydesAlzheimer&aposs DiseaseAmyloid beta-ProteinAmyotrophic Lateral SclerosisAreaAttenuatedAutophagocytosisBehavioralBrainBrain regionCarboxylic AcidsCellsDNA Sequence AlterationDeaminationDeep Brain StimulationDefectDegradation PathwayDependovirusDiseaseDistantDopamineDown-RegulationElectrophysiology (science)EnzymesExhibitsFamilyGeneticHigh PrevalenceHistologicHistologyHumanHydrogen PeroxideIn VitroInjectionsInterneuronsLevodopaLewy BodiesLysosomesMetabolicMidbrain structureMissense MutationMolecularMonoamine OxidaseMotorMovementMovement DisordersMusNatureNerve DegenerationNeurodegenerative DisordersNeuronsNeurotransmittersParkinson DiseaseParkinson&aposs Disease PathwayPathologicPathologyPathway interactionsPatternPeriodicityPharmaceutical PreparationsPropertyProteinsRoleSiteSubstantia nigra structureSymptomsTestingTimeTransgenic MiceUp-RegulationValidationWild Type Mousealdehyde dehydrogenasesalpha synucleincytotoxicdopaminergic neuronexperimental studyin vivoinsightloss of functionmisfolded proteinmouse modelneuron lossnovel therapeuticsoverexpressionoxidationpars compactapolymerizationpreventprion-likeprotein TDP-43protein aggregationprotein degradationrecessive genetic traitrelating to nervous systemside effectsynucleinopathytau Proteinstooltransmission process
项目摘要
Project Summary:
Parkinson’s disease (PD) is characterized by a progressive loss of midbrain dopaminergic neurons in
the substantia nigra pars compacta (SNpc), resulting in movement defects. A variety of dominant and
recessive genetic mutations have recently been identified in families with a high prevalence of PD (fPD),
accounting for ~15% of all PD cases. A defining pathological feature of both fPD and sporadic PD is the
presence of intracellular protein aggregates termed Lewy bodies (LB), whose major component is the protein
alpha-synuclein (α-syn). Interestingly, α-syn has recently been hypothesized to exhibit certain ‘prion-like’
properties, such as the ability to spread through the brain and trigger α-syn aggregation in interconnected brain
regions. Moreover, local injection of α-syn fibrils into the brains of wild type (WT) mice leads to aggregation of
α-syn within neurons of connected regions distant from the injection site. Together, these findings indicate
that α-syn can be taken up by neurons and transmitted to other neurons in interconnected brain areas, where
it can trigger aggregation.
Although considerable progress has been made in support of the progressive nature of α-syn
pathology, the mechanism controlling of α-syn aggregation remains poorly understood. Recent studies have
suggested that autophagic and endosomal pathways are involved. However, these general protein degradation
pathways are ubiquitously expressed in all cells, targeting these pathways may cause severe side effects.
Therefore, it is critical to identify dopamine neuron specific pathway that is critical for regulating α-syn
aggregation. One unique role of dopaminergic neurons is to synthesize and metabolize the neurotransmitter,
dopamine. The metabolic product of dopamine, 3,4-dihydroxyphenylacetaldehyde (DOPAL), is highly reactive
and promote cytotoxic polymerization of PD-related α-syn. We hypothesize that enhancing aldehyde
dehydrogenase 1a1 (ALDH1a1) – the key enzyme involved in oxidation of DOPAL in dopamine neurons-
would decrease α-syn burden in vivo thereby attenuating neuronal and behavioral defects associated with
synucleinopathy. We will examine 1) whether ALDH1a1 loss of function would enhance α-syn aggregation in
vivo; 2) whether inhibiting upstream enzyme monoamine oxidase (MAO) would decrease α-syn aggregation
and α-syn fibril propagation; 3) whether overexpression or elevate ALDH1a1 function would be beneficial to
protect dopamine neuron against α-syn aggregation.
Completion of this study will provide important validation of ALDH1a1 as a viable target for Parkinson’s
disease therapy. Ultimately, the proposed experiments will be a major step towards the understanding of
transmission and aggregation of α-syn in Parkinson’s disease.
项目概要:
帕金森病(PD)的特征是中脑多巴胺能神经元的进行性丧失,
黑质神经节(SNpc),导致运动缺陷。各种各样的优势和
最近在PD(fPD)高患病率的家族中鉴定出隐性遗传突变,
占所有PD病例的约15%。fPD和散发性PD的一个定义性病理特征是
存在称为路易体(LB)的细胞内蛋白质聚集体,其主要成分是蛋白质
α-突触核蛋白(α-syn)。有趣的是,α-syn最近被假设表现出某种“朊病毒样”
特性,例如在大脑中传播并在相互连接的大脑中触发α-syn聚集的能力
地区此外,将α-syn原纤维局部注射到野生型(WT)小鼠的脑中导致α-syn原纤维的聚集。
远离注射部位的连接区域的神经元内的α-syn。总之,这些发现表明
α-syn可以被神经元吸收,并传递到相互连接的大脑区域中的其他神经元,
它可以触发聚合。
虽然在支持α-syn的渐进性方面取得了相当大的进展,
病理学上,控制α-syn聚集的机制仍然知之甚少。最近的研究
表明自噬和内体途径参与其中。然而,这些一般的蛋白质降解
由于这些通路在所有细胞中普遍表达,因此靶向这些通路可能会导致严重的副作用。
因此,确定多巴胺神经元特异性通路对调节α-syn至关重要,
聚合来多巴胺能神经元的一个独特作用是合成和代谢神经递质,
多巴胺多巴胺的代谢产物,3,4-二羟基苯乙醛(DOPAL),是高度反应性的
并促进PD相关α-syn的细胞毒性聚合。我们假设,
脱氢酶1a 1(ALDH 1a 1)-多巴胺神经元中DOPAL氧化的关键酶-
将减少体内α-syn负荷,从而减轻与以下相关的神经元和行为缺陷:
共核蛋白病我们将研究1)ALDH 1a 1功能丧失是否会增强α-syn聚集,
体内; 2)抑制上游酶单胺氧化酶(MAO)是否会减少α-syn聚集
和α-syn纤维增殖; 3)是否过表达或提高ALDH 1a 1功能将有利于
保护多巴胺神经元免受α-syn聚集。
这项研究的完成将为ALDH 1a 1作为帕金森病的可行靶点提供重要的验证。
疾病治疗最终,拟议中的实验将是朝着理解
帕金森病中α-syn的传递和聚集。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Jun Ding其他文献
Jun Ding的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Jun Ding', 18)}}的其他基金
Fast Multi-Functional 3D Imaging of Cellular Activities in Deep Tissue
深层组织细胞活动的快速多功能 3D 成像
- 批准号:
10861526 - 财政年份:2023
- 资助金额:
$ 37.83万 - 项目类别:
Connectivity, activity, and function of a hypothalamic pathway in female social behaviors
女性社会行为中下丘脑通路的连接性、活动和功能
- 批准号:
10399638 - 财政年份:2021
- 资助金额:
$ 37.83万 - 项目类别:
Connectivity, activity, and function of a hypothalamic pathway in female social behaviors
女性社会行为中下丘脑通路的连接性、活动和功能
- 批准号:
10570861 - 财政年份:2021
- 资助金额:
$ 37.83万 - 项目类别:
Massively parallel microwire arrays for deep brain stimulation
用于深部脑刺激的大规模并行微线阵列
- 批准号:
9768582 - 财政年份:2018
- 资助金额:
$ 37.83万 - 项目类别:
Dopamine Degradation Pathway and Alpha-synuclein Aggregation
多巴胺降解途径和 α-突触核蛋白聚集
- 批准号:
9770570 - 财政年份:2017
- 资助金额:
$ 37.83万 - 项目类别:
Dopamine Degradation Pathway and Alpha-synuclein Aggregation
多巴胺降解途径和 α-突触核蛋白聚集
- 批准号:
10221065 - 财政年份:2017
- 资助金额:
$ 37.83万 - 项目类别:
Alcohol disrupts the balance between dopamine and GABA co-released by midbrain dopamine neurons
酒精破坏中脑多巴胺神经元共同释放的多巴胺和 GABA 之间的平衡
- 批准号:
10172801 - 财政年份:2017
- 资助金额:
$ 37.83万 - 项目类别:
Dopamine modulation of synaptic plasticity and integration in the striatum
多巴胺对纹状体突触可塑性和整合的调节
- 批准号:
10607794 - 财政年份:2015
- 资助金额:
$ 37.83万 - 项目类别:
Dopamine modulation of synaptic plasticity and integration in the striatum
多巴胺对纹状体突触可塑性和整合的调节
- 批准号:
10709024 - 财政年份:2015
- 资助金额:
$ 37.83万 - 项目类别:
Functional organization of neural circuits underlying movement control
运动控制背后的神经回路的功能组织
- 批准号:
8501706 - 财政年份:2011
- 资助金额:
$ 37.83万 - 项目类别:
相似海外基金
Unraveling the Dynamics of International Accounting: Exploring the Impact of IFRS Adoption on Firms' Financial Reporting and Business Strategies
揭示国际会计的动态:探索采用 IFRS 对公司财务报告和业务战略的影响
- 批准号:
24K16488 - 财政年份:2024
- 资助金额:
$ 37.83万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Mighty Accounting - Accountancy Automation for 1-person limited companies.
Mighty Accounting - 1 人有限公司的会计自动化。
- 批准号:
10100360 - 财政年份:2024
- 资助金额:
$ 37.83万 - 项目类别:
Collaborative R&D
Accounting for the Fall of Silver? Western exchange banking practice, 1870-1910
白银下跌的原因是什么?
- 批准号:
24K04974 - 财政年份:2024
- 资助金额:
$ 37.83万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
CPS: Medium: Making Every Drop Count: Accounting for Spatiotemporal Variability of Water Needs for Proactive Scheduling of Variable Rate Irrigation Systems
CPS:中:让每一滴水都发挥作用:考虑用水需求的时空变化,主动调度可变速率灌溉系统
- 批准号:
2312319 - 财政年份:2023
- 资助金额:
$ 37.83万 - 项目类别:
Standard Grant
A New Direction in Accounting Education for IT Human Resources
IT人力资源会计教育的新方向
- 批准号:
23K01686 - 财政年份:2023
- 资助金额:
$ 37.83万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
An empirical and theoretical study of the double-accounting system in 19th-century American and British public utility companies
19世纪美国和英国公用事业公司双重会计制度的实证和理论研究
- 批准号:
23K01692 - 财政年份:2023
- 资助金额:
$ 37.83万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
An Empirical Analysis of the Value Effect: An Accounting Viewpoint
价值效应的实证分析:会计观点
- 批准号:
23K01695 - 财政年份:2023
- 资助金额:
$ 37.83万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Accounting model for improving performance on the health and productivity management
提高健康和生产力管理绩效的会计模型
- 批准号:
23K01713 - 财政年份:2023
- 资助金额:
$ 37.83万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
New Role of Not-for-Profit Entities and Their Accounting Standards to Be Unified
非营利实体的新角色及其会计准则将统一
- 批准号:
23K01715 - 财政年份:2023
- 资助金额:
$ 37.83万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Improving Age- and Cause-Specific Under-Five Mortality Rates (ACSU5MR) by Systematically Accounting Measurement Errors to Inform Child Survival Decision Making in Low Income Countries
通过系统地核算测量误差来改善特定年龄和特定原因的五岁以下死亡率 (ACSU5MR),为低收入国家的儿童生存决策提供信息
- 批准号:
10585388 - 财政年份:2023
- 资助金额:
$ 37.83万 - 项目类别: