SARM1 functional polymorphisms and their contribution to ALS risk
SARM1 功能多态性及其对 ALS 风险的影响
基本信息
- 批准号:10320381
- 负责人:
- 金额:$ 62.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:ALS pathologyALS patientsAffectAllelesAmino AcidsAmyotrophic Lateral SclerosisAttenuatedAxonBiological AssayCategoriesCell DeathCessation of lifeChemicalsClustered Regularly Interspaced Short Palindromic RepeatsComplexDataDevelopmentDiseaseDisease modelDominant-Negative MutationEnzymesEtiologyFaceFoundationsFunctional disorderGeneral PopulationGenesGenetic PolymorphismGenetic VariationGenetic studyHumanHuman GeneticsInjuryInvestigationKnock-inKnock-in MouseKnockout MiceLinkLongevityMaintenanceMediatingMessenger RNAMetabolicMethodsModelingMolecularMotorMotor NeuronsMusMuscleMutateMutationNAD+ NucleosidaseNerve DegenerationNervous system structureNeuronsNeuropathyParalysedPathogenesisPathogenicityPathologyPathway interactionsPhenotypeProcessProteinsRiskRoleRouteSpinal CordStructureSymptomsTDP-43 aggregationTestingTherapeuticTraumaVariantViralaxon injuryaxonal degenerationbasecohortdisorder riskdruggable targetenzyme activityexperimental studyfallsgain of functiongain of function mutationgene therapygenetic risk factorgenetic variantgenome wide association studygenotyped patientsinduced pluripotent stem cellinhibitor therapyinnovationloss of functionmembermotor disordermouse modelneurodegenerative phenotypeneuron lossnoveloverexpressionprogramsprotein TDP-43small molecule inhibitorsuperoxide dismutase 1
项目摘要
Motor axon loss is a cardinal symptom of amyotrophic lateral sclerosis (ALS). Axon loss can be driven
by a genetically encoded program in which the axon survival factors NMNAT2 and STMN2 inhibit the activity of
the axon destruction factor SARM1. Recent data suggest that this program of axon self-destruction may
contribute to pathology in ALS. First, aggregation of TDP-43, a hallmark of most ALS cases, results in the
selective loss of mRNA encoding functional STMN2, a key axon survival factor. Second, loss of SARM1
suppresses some neurodegenerative phenotypes in a mouse ALS model that expresses pathogenic human
TDP-43. Here we investigate the contribution of this axon degeneration pathway to ALS. We have defined the
mechanism of action of SARM1, demonstrating that it is the founding member of a new class of NAD-cleaving
enzymes. SARM1 enzyme activity is normally held in check via an autoinhibitory domain. Injury- or disease-
induced loss of NMNAT2 and STMN2 disinhibits SARM1, leading to rapid NAD+ depletion, metabolic
catastrophe, and axon fragmentation. Our structure-function studies of the SARM1 protein have identified
mutations with a range of consequences, from constitutively active variants that promote cell death and axon
loss, to dominant negative variants that are neuroprotective. These findings imply that human variants may exist
that either promote or protect against neurodegeneration, and that understanding the phenotypic consequences
of genetic variation requires functional studies of enzyme activity. In support of this hypothesis, we have identified
several rare SARM1 variants in ALS patients, but not in controls, that have constitutive NADase activity and
promote neuron death and axon loss. These variants also cause motor dysfunction and paralysis when
expressed in the mouse CNS, suggesting that activating SARM1 mutations may contribute to ALS pathogenesis.
Here we propose to define the function of SARM1 variants from ALS patients, controls, and the general
population. These studies will allow us to categorize SARM1 variants as putatively pro-degenerative,
neuroprotective, or neutral. In parallel, we will dissect the contribution of variation in components of the
programmed axon destruction pathway to ALS phenotypes, alone and in combination with known ALS genetic
risk-factors, in motor neurons differentiated from human induced pluripotent stem cells (iPSCs). Finally, we will
investigate neurodegeneration in a mouse knock-in model carrying a Sarm1 allele equivalent to a pro-
degenerative allele found in ALS patients, alone and in combination with a SOD1 model, based on a specific
patient genotype that we identified. We will attempt to suppress ALS phenotypes with SARM1 inhibition via a
proven gene therapy approach and with experimental small molecule inhibitors. Results of these studies will
establish the relationship between the SARM1-mediated axon destruction program and ALS, and build the
foundation to develop axoprotective therapeutics to treat this devastating disease.
运动轴突丧失是肌萎缩性侧索硬化症(ALS)的主要症状。轴突损失可以被驱动
项目成果
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ADAM JOSEPH BLOOM其他文献
ADAM JOSEPH BLOOM的其他文献
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{{ truncateString('ADAM JOSEPH BLOOM', 18)}}的其他基金
SARM1 functional polymorphisms and their contribution to ALS risk
SARM1 功能多态性及其对 ALS 风险的影响
- 批准号:
10533327 - 财政年份:2021
- 资助金额:
$ 62.01万 - 项目类别:
NOVEL APPROACHES TO INVESTIGATE GENETIC CORRELATES OF SMOKING BEHAVIORS
研究吸烟行为遗传相关性的新方法
- 批准号:
9246511 - 财政年份:2014
- 资助金额:
$ 62.01万 - 项目类别:
NOVEL APPROACHES TO INVESTIGATE GENETIC CORRELATES OF SMOKING BEHAVIORS
研究吸烟行为遗传相关性的新方法
- 批准号:
8828651 - 财政年份:2014
- 资助金额:
$ 62.01万 - 项目类别:
NOVEL APPROACHES TO INVESTIGATE GENETIC CORRELATES OF SMOKING BEHAVIORS
研究吸烟行为遗传相关性的新方法
- 批准号:
9039020 - 财政年份:2014
- 资助金额:
$ 62.01万 - 项目类别:
NOVEL APPROACHES TO INVESTIGATE GENETIC CORRELATES OF SMOKING BEHAVIORS
研究吸烟行为遗传相关性的新方法
- 批准号:
8634957 - 财政年份:2014
- 资助金额:
$ 62.01万 - 项目类别:
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