Pum2-dependent translational regulation of a-SYN near mitochondria and contribution to the pathogenesis of Parkinson's disease
Pum2-dependent translational regulation of a-SYN near mitochondria and contribution to the pathogenesis of Parkinson's disease
批准号:
10408162
负责人:
YOON-SEONG KIM
金额:
$34.34万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-09-15 至 2024-05-31
关键词:
3&apos Untranslated RegionsAffectAutopsyBindingBiochemicalBrain DiseasesCRISPR/Cas technologyComplexDNA Sequence AlterationData ReportingDevelopmentElementsFYN geneFamilyGoalsHumanImageIn VitroInner mitochondrial membraneLabelLengthLinkMediatingMessenger RNAMissionMitochondriaMitochondrial ProteinsMolecularMonitorMorphologyNADH dehydrogenase (ubiquinone)National Institute of Neurological Disorders and StrokeNuclearOuter Mitochondrial MembraneOxidative StressParkinson DiseasePathogenesisPersonsPlayPolyribosomesProtein translocationProteinsPublic HealthQuality of lifeRNA BindingRNA Recognition MotifRNA-Binding ProteinsReactive Oxygen SpeciesRegulationRegulatory ElementResearchRoleSingle Nucleotide PolymorphismSurfaceTechniquesTestingToxic effectTrans-ActivatorsTranscriptTranslatingTranslational RegulationTranslational RepressionTranslationsUnited States National Institutes of HealthUntranslated RegionsYeastsalpha synucleinbasegenome editingimprovedin vivomitochondrial dysfunctionnovelnovel therapeuticsoverexpressionparalogous gene
中文摘要
α-突触核蛋白(α-SYN)和线粒体功能障碍是帕金森病(PD)发病机制中的两个重要组成部分。线粒体功能障碍是PD发病机制多次迭代的共同特征,而α-SYN毒性对线粒体的影响似乎最为显着。α-SYN与线粒体之间复杂的相互作用已被广泛观察到。虽然线粒体和α-SYN之间的复杂相互作用尚不清楚,但我们的初步研究表明,α-SYN mRNA的3‘-非翻译区在线粒体附近的α-SYN的翻译调控中起着关键作用。我们的初步发现表明:1)α-SYN mRNA定位于线粒体表面,在那里其翻译是由线粒体ROS启动的;2)这种翻译控制是由Pum2调控的,它与α-SYN转录本的3‘-非翻译区(3’-UTR)结合;3)有趣的是,死后PD脑中线粒体Pum2的水平显著低于对照组,而α-SYN的水平则相反,这表明Pum2对线粒体附近的α-SYN具有S抑制作用。此外,最近的研究表明α-SYN3‘-UTR单核苷酸多态与帕金森病的关系强烈提示,3’-非编码区对α-SYN的调节可能成为帕金森病发病的关键因素。我们的中心假设是,Pum2介导的线粒体外表面α-SYN翻译抑制的解除调控有助于观察到PD患者的线粒体功能障碍。将追求以下三个具体目标:在目标1中,将确定负责α-SYN线粒体定位的顺式调控元件和反式因子。在目标2中,将确定线粒体ROS如何控制Pum2介导的α-SYN mRNA的翻译以及新合成的α-SYN的作用。在目标3中,将研究α-SYN3‘-非编码区中与PD相关的SNPs是否导致Pum2结合、蛋白质转位到线粒体和线粒体功能的变化。该项目的成功完成可能会通过阐明Pum2和α-SYN的3‘-非编码区在翻译调控中的作用,为我们理解在PD发病机制中控制线粒体附近α-SYN表达的分子机制创造一个范式转变
英文摘要
Alpha-synuclein (α-SYN) and mitochondrial dysfunction are two central components in Parkinson's disease (PD) pathogenesis. Mitochondrial dysfunction is a common feature of the many iterations of PD pathogenesis and α-SYN toxicity seems to affect mitochondria most significantly. Complex interplay between α-SYN and mitochondria has been widely observed. While the intricate crosstalk between mitochondria and α-SYN is poorly understood, our preliminary studies suggest that the 3'-untranslated region (3'-UTR) of α-SYN mRNA plays a key role in translational regulation of α-SYN near mitochondria. Our preliminary findings demonstrate that 1) α-SYN mRNA is localized to the mitochondrial surface where its translation is initiated by mitochondrial ROS; 2) this translational control is governed by Pum2, a RNA-binding translational repressor, which binds to the 3'-untranslated region (3'-UTR) of α-SYN transcript; 3) interestingly, mitochondrial Pum2 levels in post-mortem PD brain were significantly lower compared to control subjects, while α-SYN levels were opposite, implying Pum2’s repressive role on α-SYN near mitochondria. In addition, recent studies showing the association of single nucleotide polymorphisms in the α-SYN 3'-UTR with PD strongly suggest that 3`-UTR-mediated regulation of α-SYN could become a critical player in PD pathogenesis. Our central hypothesis is that deregulation of Pum2-mediated α-SYN translational repression on the outer surface of mitochondria contributes to mitochondrial dysfunction observed in PD. The following three specific aims will be pursued: In Aim 1, both the cis-regulatory elements and the trans- factors responsible for mitochondrial localization of α-SYN will be identified. In Aim 2, it will be determined how mitochondrial ROS controls Pum2-mediated translation of α-SYN mRNA and the roles of newly synthesized α- SYN. In Aim 3, it will be investigated whether PD-associated SNPs in the 3'-UTR of α-SYN cause changes in Pum2 binding, translocation of the protein to mitochondria, and mitochondrial functions. The successful completion of this project could create a paradigm shift in our understanding of molecular mechanisms that control α-SYN expression near mitochondria in PD pathogenesis by elucidating the role of Pum2 and the 3'-UTR of α-SYN in translational regulation
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海外基金