USP30 Inhibition as a Therapeutic Strategy in Parkinson's Disease
USP30 Inhibition as a Therapeutic Strategy in Parkinson's Disease
批准号:
10809860
负责人:
DAVID K. SIMON
金额:
$47.55万
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:
2023-09-01 至 2025-08-31
关键词:
AttenuatedAutophagocytosisAutophagosomeBehavior assessmentBindingBiogenesisBrainBrain DiseasesCellsChimeric ProteinsClinicalComplexDataDefectDeubiquitinating EnzymeDiseaseDoseDrosophila genusElectron TransportFluorescenceFunctional disorderGene MutationHomeostasisImpairmentInjectionsKnockout MiceLinkMaintenanceMediatingMitochondriaMitochondrial ProteinsModelingMolecularMusNerve DegenerationNeuronsOuter Mitochondrial MembraneOxidative StressPINK1 geneParkinParkinson DiseasePathway interactionsProtein ImportProteinsReactive Oxygen SpeciesRoleSmall Interfering RNASubstantia nigra structureSystemTestingTherapeuticToxic effectUbiquitinUp-RegulationValidationalpha synucleinautosomebrain celldopaminergic neuronexperimental studyin vivoinhibitorknock-downmitochondrial dysfunctionmitochondrial membranemotor behaviormouse modelneuron lossneuroprotectionnigrostriatal pathwayoxidative damagepharmacologicresponsesmall molecular inhibitorsmall moleculeubiquitin isopeptidase
中文摘要
大量的证据表明线粒体稳态功能障碍是一个关键的病理生理
英文摘要
A large body of evidence implicates dysfunction of mitochondrial homeostasis as a key pathophysiological
mechanism in Parkinson’s disease (PD). Maintenance of a pool of healthy functioning mitochondria requires a
system for selectively degrading dysfunctional mitochondria (“mitophagy”). Autosomal recessive (AR) PD due
to Parkin deficiency links directly to a defect in mitophagy. Mitochondrial dysfunction causes Parkin to
translocate to the outer mitochondrial membrane where it interacts with PINK1 (another gene where mutations
cause AR PD) to ubiquitinate mitochondrial proteins, thereby inducing fusion of mitochondria with
autophagosomes, followed by autophagic degradation. Thus, loss of Parkin leads to the accumulation of
dysfunctional mitochondria due to impaired mitophagy. . In this context, we hypothesize that enhancing
mitophagy will protect against α-synuclein (αSyn) toxicity ΑSyn induces mitochondrial complex I dysfunction,
potentially by directly binding to TOM20 on the mitochondrial membrane and thereby interfering with
mitochondrial protein import. Conversely, dysfunctional mitochondria produce increased reactive oxygen
species (ROS), consistent with increased markers of oxidative damage in the PD brain. Furthermore, ROS can
increase αSyn accumulation. However, the role of mitophagy in clearing away dysfunctional mitochondria in
the setting of αSyn induced mitochondrial impairment is unknown. USP30 is a deubiquitinating enzyme (DUB)
tethered to the outer mitochondrial membrane, where it directly removes ubiquitin that had been attached by
Parkin, thereby counteracting Parkin’s ability to promote mitophagy. Knock-down of USP30 by siRNA rescues
mitophagy in Parkin-deficient cells and protects dopaminergic (DA) neurons in Parkin-deficient Drosophila. And
our preliminary data suggest that USP30 knock-out mice show enchanced mitophagy and protection against
αSyn toxicity. Thus, inhibition of USP30 is an attractive therapeutic strategy for restoring mitophagy to achieve
neuroprotection in PD. These data highlight the major potential for neuroprotection in PD by specifically
modulating mitophagy through targeting of USP30. With this goal in mind, we now propose to test a highly
specific CNS-penetrant small molecular inhibitor of USP30 for neuroprotection in a slowly degenerative αSyn-
based mouse model of PD, and to assess the degree to which αSyn clearance and neuroprotection relates to
the impact of USP30 inhibition on specific pathways mediating αSyn degradation. These results could provide
support for moving forward with MTX012 or other brain-penetrant pharmacological USP30 inhibitors towards
clinical neuroprotection studies in PD.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Mitochondrial mechanisms and vulnerability to alpha-synuclein toxicity
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批准号:9385532
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项目类别:
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资助金额:$21.63万
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财政年份:2017
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负责人:DAVID K. SIMON
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依托单位:
PGC-1alpha and Pitx3 as individual and combined targets for neuroprotection
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批准号:9256551
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资助金额:$38.0万
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财政年份:2014
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负责人:DAVID K. SIMON
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依托单位:
PGC-1alpha and Pitx3 as individual and combined targets for neuroprotection
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批准号:8828821
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资助金额:$37.87万
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财政年份:2014
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负责人:DAVID K. SIMON
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PGC-1alpha and Pitx3 as individual and combined targets for neuroprotection
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批准号:8710863
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项目类别:
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资助金额:$39.22万
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财政年份:2014
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负责人:DAVID K. SIMON
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依托单位:
PGC-1alpha and Pitx3 as individual and combined targets for neuroprotection
-
批准号:9049558
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项目类别:
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资助金额:$38.0万
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财政年份:2014
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负责人:DAVID K. SIMON
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依托单位:
Mechanisms of Protection in the Brain by Physical Exercise in Polg Mutator Mice
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批准号:8453923
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资助金额:$26.1万
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财政年份:2012
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负责人:DAVID K. SIMON
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依托单位:
Mechanisms of Protection in the Brain by Physical Exercise in Polg Mutator Mice
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批准号:8550835
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项目类别:
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资助金额:$20.99万
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财政年份:2012
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负责人:DAVID K. SIMON
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依托单位:
Mitophagy-driven selection against heteroplasmic mitochondrial DNA mutations
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批准号:8323862
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项目类别:
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资助金额:$21.75万
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财政年份:2011
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负责人:DAVID K. SIMON
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依托单位:
Mitophagy-driven selection against heteroplasmic mitochondrial DNA mutations
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批准号:8258212
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项目类别:
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资助金额:$25.51万
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财政年份:2011
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负责人:DAVID K. SIMON
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依托单位:
Impact of Somatic Mitochondrial DNA Point Mutations in the Aging Brain
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批准号:8118522
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项目类别:
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资助金额:$7.36万
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财政年份:2010
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负责人:DAVID K. SIMON
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依托单位:
Impact of Somatic Mitochondrial DNA Point Mutations in the Aging Brain
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批准号:7989475
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项目类别:
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资助金额:$7.65万
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财政年份:2010
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负责人:DAVID K. SIMON
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依托单位:
Oxidative Stress, alpha-Synuclein, and mtDNA Mutations in Parkinson's Disease
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批准号:7370030
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项目类别:
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资助金额:$22.31万
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财政年份:2007
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负责人:DAVID K. SIMON
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依托单位:
Oxidative Stress, alpha-Synuclein, and mtDNA Mutations in Parkinson's Disease
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批准号:7596866
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项目类别:
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资助金额:$29.75万
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财政年份:2007
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负责人:DAVID K. SIMON
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依托单位:
Oxidative Stress, alpha-Synuclein, and mtDNA Mutations in Parkinson's Disease
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批准号:7502597
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项目类别:
-
资助金额:$29.75万
-
财政年份:2007
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负责人:DAVID K. SIMON
-
依托单位:
Oxidative Stress, alpha-Synuclein, and mtDNA Mutations in Parkinson's Disease
-
批准号:7800926
-
项目类别:
-
资助金额:$29.45万
-
财政年份:2007
-
负责人:DAVID K. SIMON
-
依托单位:
Oxidative Stress, alpha-Synuclein, and mtDNA Mutations in Parkinson's Disease
-
批准号:8055402
-
项目类别:
-
资助金额:$29.16万
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财政年份:2007
-
负责人:DAVID K. SIMON
-
依托单位:
Somatic Mitochondrial DNA Mutations in Neurons and Glia
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批准号:7272791
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项目类别:
-
资助金额:$8.25万
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财政年份:2006
-
负责人:DAVID K. SIMON
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依托单位:
Somatic Mitochondiral DNA Mutations in Neurons and Glia
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批准号:7144707
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项目类别:
-
资助金额:$8.5万
-
财政年份:2006
-
负责人:DAVID K. SIMON
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依托单位:
Parkinson Disease Neuroprotection Clinical Trial
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批准号:7046678
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项目类别:
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资助金额:$2.09万
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财政年份:2002
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负责人:DAVID K. SIMON
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依托单位:
Parkinson Disease Neuroprotection Clinical Trial
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批准号:7166757
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项目类别:
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资助金额:$2.84万
-
财政年份:2002
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负责人:DAVID K. SIMON
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依托单位: