Dynamin-related protein 1 and mitochondrial fission adapters regulate presynaptic function
Dynamin-related protein 1 and mitochondrial fission adapters regulate presynaptic function
批准号:
10660812
负责人:
ROBERT B RENDEN
金额:
$45.02万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-09-18 至 2028-08-31
关键词:
AcuteAdaptor Signaling ProteinAdjuvantAffectAgingAlzheimer&aposs DiseaseBasic ScienceBiogenesisBiological ModelsBrainCell SurvivalCell membraneCell physiologyCellsCellular StressChronicCollaborationsDataDefectDevelopmentDiseaseDisease ProgressionDissectionDynaminDynamin IIIElectric CapacitanceElectron MicroscopyElectrophysiology (science)EmbryoEndocytosisEnvironmentExcisionExcitatory SynapseFluorescenceFunctional disorderGene Transfer TechniquesGlutamatesGoalsHealthHomeostasisHumanHuntington DiseaseImpairmentInterventionInvestigationKnowledgeMeasurementMediatingMembraneMitochondriaModelingMorphologyMotivationMusNerve DegenerationNervous SystemNeurodegenerative DisordersNeuronsOrganismOuter Mitochondrial MembranePhenotypePlasmaPlayPopulationPreparationPresynaptic TerminalsProcessProtein IsoformsProteinsReactive Oxygen SpeciesRecyclingRegulationResearchResearch PersonnelResolutionRespirationRetrievalRoleRouteShapesSiteSliceStressSynapsesSynaptic TransmissionSynaptic VesiclesTestingTherapeuticTimeTissuesViralWorkage relatedelectron tomographyfunctional restorationhealthspanlight microscopyloss of functionmitochondrial dysfunctionnanoscalenervous system disorderneurotransmissionnovel strategiespostnatalpresynapticpresynaptic neuronsreconstructionrecruitresponsestressorsynaptic functiontherapeutic target
中文摘要
该项目的长期目标是改善线粒体功能障碍导致的神经传递缺陷,
作为阻止疾病进展到后期退行性阶段的一种方法,延长人群的健康寿命
越来越多的人受到与年龄相关的神经系统疾病的影响。动力相关蛋白 1 (DRP1) 的作用是促进
线粒体裂变,并已被确定为限制异常线粒体的治疗靶点
阿尔茨海默氏症和亨廷顿舞蹈症的碎片化。该项目的目标是确定 DRP1 如何
与线粒体裂变接头的相互作用影响突触前末端功能。我们建议需要
高水平的线粒体呼吸以支持突触传递,使突触前末端成为
高细胞应激环境。调节线粒体裂变对于响应细胞生存至关重要
细胞应激源,通过 DRP1 起作用,但神经元突触前末端使用的适配器是
未知。在具体目标 1 中,我们将研究线粒体裂变接头蛋白 MFF 和
FIS1 影响线粒体稳态和突触传递。在具体目标 2 中,我们将研究不同的
DRP1被消除时线粒体功能和超微结构的参数,并尝试挽救功能
通过将 DRP1 重新表达靶向线粒体外膜。表型差异将与
目标 1 中的目标是全面了解受调节的线粒体裂变对突触功能的影响。
DRP1 还可能促进突触处质膜的分裂,但这种附加功能的影响
关于突触传递的问题尚未解决。在具体目标 3 中,我们将检验 DRP1 促进的假设
突触小泡的回收和回收,并确定膜相关的 DRP1 是否足以
促进 SV 恢复并恢复突触传递。 PI 和另外两个世界级的合作
研究人员开发了新的方法来剖析 DRP1 的亚型特异性作用,使用
Held 的小鼠花萼作为模型系统。使用病毒介导的转基因组合,先进
电生理学、高分辨率光学和电子显微镜、特定 DRP1 亚型的能力
支持线粒体裂变与突触传递和突触前 SV 恢复将被系统地
已测试。与小型传统突触相比,巨型“花萼状”兴奋性突触的实验可及性
突触允许从突触前末端进行记录,从而允许操纵突触前 [ATP] 和
实时跟踪膜外吞/内吞作用。这种方法对于剖析能量支持是必要的。
突触线粒体的作用来自突触小泡回收的机制。该项目的结果
可用于告知、预测和测试传统谷氨酸突触的功能和功能障碍,其中
首先出现与疾病相关的神经变性。该项目产生的知识将确定可行的
恢复 DRP1 功能改变的突触功能的干预途径,可以利用
治疗上可减轻疾病相关的突触功能障碍和神经变性。
英文摘要
The long-term goal of this project is to ameliorate neurotransmission defects due to mitochondrial dysfunction,
as a way to stop disease progression to later degenerative stages, increasing healthspan in populations
increasingly subject to age-related neurological diseases. Dynamin-related protein 1 (DRP1) acts to promote
mitochondrial fission and has been identified as a therapeutic target for limiting aberrant mitochondrial
fragmentation in Alzheimer’s and Huntington’s disease. The goal of this project is to determine how DRP1
interaction with mitochondrial fission adapters impacts presynaptic terminal function. We propose that the need
for high levels of mitochondrial respiration to support synaptic transmission makes the presynaptic terminal a
high cellular stress environment. Regulated mitochondrial fission is important for cell survival in response to
cellular stressors, acting through DRP1, but the adapters utilized at the neuronal presynaptic terminal are
unknown. In Specific Aim 1, we will examine how loss of the mitochondrial fission adapter proteins MFF and
FIS1 affect mitochondria homeostasis and synaptic transmission. In Specific Aim 2, we will examine distinct
parameters of mitochondrial function and ultrastructure when DRP1 is eliminated, and attempt to rescue function
by targeting DRP1 re-expression to mitochondrial outer membrane. Phenotypic differences will be corelated with
those in Aim 1, to generate a complete picture of the effect of regulated mitochondrial fission on synaptic function.
DRP1 may also facilitate scission of plasma membrane at the synapse, but the impact of this additional function
on synaptic transmission is unresolved. In Specific Aim 3, we will test the hypothesis that DRP1 facilitates
synaptic vesicle retrieval and recycling, and determine whether membrane-associated DRP1 is sufficient to
facilitate SV retrieval, and restore synaptic transmission. In collaboration, the PI and two other world-class
investigators have developed novel approaches to allow dissection of the isoform-specific role(s) of DRP1, using
the mouse calyx of Held as a model system. Using a combination of viral-mediated transgenesis, advanced
electrophysiology, and high-resolution light and electron microscopy, the ability of specific DRP1 isoforms to
support mitochondrial fission versus synaptic transmission and presynaptic SV retrieval will be systematically
tested. In contrast to small conventional synapses, experimental accessibility of giant ‘calyx-like’ excitatory
synapses allow recordings from the presynaptic terminal, permitting manipulation of presynaptic [ATP] and
tracking membrane exo/endocytosis in real time. This approach is necessary to dissect the energy-supporting
roles of synaptic mitochondria from mechanisms underlying synaptic vesicle recycling. Results from this project
can be used to inform, predict, and test function and dysfunction at conventional glutamatergic synapses where
disease-relevant neurodegeneration first appears. Knowledge generated from this project will identify viable
routes of intervention for restoring function to synapses where DRP1 function is altered, which can be leveraged
therapeutically to alleviate disease-related synaptic dysfunction and neurodegeneration.
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