The Regulation of Synaptic Connectivity and Homeostasis by Huntingtin
The Regulation of Synaptic Connectivity and Homeostasis by Huntingtin
批准号:
9083719
负责人:
Cagla Eroglu
金额:
$34.25万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-02-01 至 2020-11-30
关键词:
AdultAffectAgeAstrocytesAutomobile DrivingBindingBrainCalcium ChannelCellsCorpus striatum structureDefectDevelopmentDiseaseDisease ProgressionDisease modelDominant-Negative MutationEnsureExcitatory SynapseFunctional disorderGlutamatesGlutamineGoalsHealthHereditary DiseaseHomeostasisHuntington DiseaseHuntington geneImpaired healthImpairmentIn VitroIndividualKnock-in MouseLeadLengthLifeLongevityMaintenanceMediatingMolecularMonitorMovementMusMutationNerve DegenerationNeurodegenerative DisordersNeurogliaNeurologicNeuronsOnset of illnessOutcomePathway interactionsPatientsPlayPreventionProcessProtein FamilyPublishingRegulationReportingRoleSignal PathwaySignal TransductionStretchingSymptomsSynapsesTestingTherapeuticToxic effectTreatment EfficacyWorkbasedisease-causing mutationgabapentingain of functioninnovationinsightknock-downloss of functionmouse modelmutantneural circuitnovelpolyglutamineprogressive neurodegenerationpublic health relevancereceptorresearch studyresponsesynaptic functionsynaptogenesis
中文摘要
英文摘要
DESCRIPTION (provided by applicant): Huntington's disease (HD) is a fatal neurodegenerative disease caused by mutations introducing an extended stretch of poly-glutamines (poly-Q) at the N-terminus of huntingtin (Htt). A widely accepted, yet unproven, hypothesis is that HD is caused by gain-of-function, toxic effects of mutant Htt protein. In recent
years, dominant negative loss-of-function effects of poly-Q mutations have also emerged as drivers of disease pathophysiology. However, despite what is known about pathophysiology of mutant Htt, the functions of wildtype (WT) Htt are still largely unknown. Astrocytes, the major glial cells of the brain, secrete synaptogenic thrombospondin family proteins to initiate synapse formation. Thrombospondin induces synaptogenesis by binding to a neuronal receptor, the gabapentin receptor α2δ-1. In our preliminary experiments, we found that α2δ-1 interacts with huntingtin and this interaction is impaired in the presence of poly-Q expansions. Early synaptic problems in the excitatory cortical and striatal connections have been reported in HD, but whether huntingtin played a role in synaptic connectivity was unknown. By conditionally silencing Htt in the mouse cortex we showed that huntingtin controls synapse formation and maturation within cortical and striatal circuits. Moreover, by using an HD mouse model, we found that this function of huntingtin is lost when the pathogenic poly-glutamine mutation is present. Based on these findings, here we will test the hypotheses that huntingtin controls synaptic connectivity through its interaction with α2δ-1, and that the impairment of this interaction in the presence of the disease-causing poly-Q mutations leads to detrimental errors in synaptic connectivity. The loss-of-function effects of mutant Htt during development may be important for driving the disease onset and could underlie prodromal neurological symptoms of HD. Therefore, understanding the function of WT Htt in synaptic development may enable us to find ways to correct the developmental errors in the cortical and striatal circuits of mutant Huntingtin carriers. This approach could therefore lead to the prevention of disease onset or greatly diminished disease progression, allowing HD patients to live full, healthy lives.
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海外基金