NADPH Oxidase 2 in Parkinson's Disease Pathogenesis
NADPH 氧化酶 2 在帕金森病发病机制中的作用
基本信息
- 批准号:10581821
- 负责人:
- 金额:$ 48.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-12-05 至 2027-11-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAnimal Disease ModelsAntisense OligonucleotidesBindingBiological AssayBiological ProcessBrainCellsComplexConsensusDataDefectDetectionDiseaseDisease modelElectron TransportEnvironmentEventExperimental DesignsExperimental ModelsFunctional disorderGenesHistologicIdiopathic Parkinson DiseaseIn SituInflammatory ResponseKnock-outLRRK2 geneLigationMediatingMicrogliaMitochondriaModelingMovement DisordersNADPNADPH OxidaseNatureNerve DegenerationNeurogliaNeuronsOutcomeOxidasesOxidation-ReductionOxidative StressParkinson DiseaseParkinsonian DisordersPathogenesisPathogenicityPathologicPathologyPatientsPersonsPhosphotransferasesPlayPost-Translational Protein ProcessingPrintingProcessProductionProtein ImportProtein IsoformsRattusReactive Oxygen SpeciesRegulatory PathwayReportingResearchResolutionRoleRotenoneSignal TransductionSourceSuperoxidesSystemTechnologyTestingTherapeuticTimeUnited StatesWorkage relatedalpha synucleindesigndopaminergic neuroneffective therapyknock-downmitochondrial dysfunctionneuroinflammationneuroprotectionnigrostriatal degenerationnon-motor symptomnovelnovel drug classnovel therapeutic interventionoverexpressionoxidative damagepathogenic isoformpharmacologicpreventresponse
项目摘要
ABSTRACT
Reductive-oxidative (redox) imbalance in nigrostriatal neurons has been indicated as an important cause of
nigrostriatal degeneration in familial and idiopathic Parkinson disease (PD). While it is generally assumed that
the oxidative damage seen in PD derives from dysfunctional mitochondrial electron transport chain, there is
growing consensus that NADPH oxidase isoform 2 (NOX2) may be important and, in some cellular systems, the
two appear intimately related in a redox regulatory pathway recently termed “ROS-induced ROS production”
(RIRP). However, the relevance of NOX2 in PD pathogenesis remains underexplored. Additionally, the in-situ
detection of NOX2 activity state has been difficult to assess. Using a novel histological proximity ligation (PL)
assay to detect NOX2 activation state with excellent cellular resolution, our preliminary findings address the
relevance of NOX2 activity, in idiopathic PD and in PD animal models of parkinsonism.
Our preliminary studies reveal that NOX2 can be activated by mitochondrially-derived ROS in a RIRP manner,
which serves to greatly amplify ROS production. The resultant NOX2 activity is necessary and sufficient to both
activate wildtype LRRK2 and to cause accumulation and oxidative post-translational modifications of α-synuclein
(4-HNE-α-syn and NO-α-syn). The NOX2-activated LRRK2 kinase activity leads to endo-lysosomal and
autophagic defects and decreased degradation of toxic species of α-synuclein, such as pSer129-α-synuclein. In
this way, NOX2 activity both drives the formation and inhibits the disposal of toxic forms of α-synuclein. In turn,
as shown in previous work, these forms of α-synuclein bind to mitochondrial TOM20, blocking protein import and
leading to mitochondrial functional alterations and relative increased ROS production. Thus, there appears to be
a feedforward cycle, in which NOX2 plays an essential amplification role in PD pathogenesis.
However, other NOXs, including isoforms 1 and 4 – also highly expressed in brain - might contribute somehow
to this pathogenic process. In this context, the current proposal is designed to further explore and define the
exclusive role of NOX2 in PD.
Positive outcomes demonstrating the relevance of NOX2 in PD pathogenesis and the efficacy of NOX2-directed
therapies using antisense oligonucleotides (ASOs), will reveal potential therapeutic strategies for
neuroprotection and ameliorate the PD-related movement disorder. As such, this project has compelling practical
significance for PD therapeutics.
摘要
黑质纹状体神经元中的还原-氧化(氧化还原)失衡已被指出是黑质纹状体损伤的重要原因。
家族性和特发性帕金森病(PD)中的黑质纹状体变性。虽然一般认为,
在PD中观察到的氧化损伤来源于功能失调的线粒体电子传递链,
越来越多的共识认为NADPH氧化酶亚型2(NOX 2)可能是重要的,在某些细胞系统中,
这两种物质在氧化还原调节途径中密切相关,最近被称为“ROS诱导的ROS产生”。
(RIRP)。然而,NOX 2在PD发病机制中的相关性仍有待研究。此外,现场
NOX 2活性状态的检测一直难以评估。使用一种新的组织学邻近结扎(PL)
检测NOX 2激活状态具有良好的细胞分辨率,我们的初步研究结果解决了
NOX 2活性在特发性PD和帕金森病PD动物模型中的相关性。
我们的初步研究表明,NOX 2可以通过RIRP方式被神经源性ROS激活,
其用于极大地放大ROS产生。由此产生的NOX 2活性是必要的,也是足够的,
激活野生型LRRK 2并引起α-突触核蛋白的积累和氧化翻译后修饰
(4-HNE-α-syn和NO-α-syn)。NOX 2激活的LRRK 2激酶活性导致内-溶酶体和
自噬缺陷和α-突触核蛋白的毒性物质如pSer 129-α-突触核蛋白的降解减少。在
通过这种方式,NOX 2活性既驱动α-突触核蛋白的形成,又抑制其毒性形式的处置。反过来,委员会认为,
如先前的工作所示,这些形式的α-突触核蛋白与线粒体TOM 20结合,阻断蛋白质输入,
导致线粒体功能改变和相对增加的ROS产生。因此,似乎有
前馈循环,其中NOX 2在PD发病机制中起重要的放大作用。
然而,其他NOX,包括亚型1和4 --也在大脑中高度表达--可能以某种方式起作用。
这一致病过程。在这方面,本提案旨在进一步探讨和界定
NOX 2在PD中的独特作用。
阳性结果证明了NOX 2在PD发病机制中的相关性以及NOX 2导向的PD治疗的疗效。
使用反义寡核苷酸(ASO)的治疗,将揭示潜在的治疗策略,
神经保护和改善PD相关的运动障碍。因此,该项目具有令人信服的实用性
对PD治疗的意义。
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)
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Roberto Di Maio其他文献
Roberto Di Maio的其他文献
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{{ truncateString('Roberto Di Maio', 18)}}的其他基金
Protective actions of the anti-inflammatory drug candidate 10-nitro-oleic acid in Parkinson’s disease
候选抗炎药物 10-硝基油酸对帕金森病的保护作用
- 批准号:
9805542 - 财政年份:2019
- 资助金额:
$ 48.36万 - 项目类别:
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