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.
运动轴突缺失是肌萎缩侧索硬化症(ALS)的主要症状。轴突缺失可导致
轴突存活因子NMNAT 2和STMN 2抑制
轴突破坏因子SARM 1。最近的数据表明,这种轴突自我毁灭的程序可能
有助于ALS的病理学改变首先,TDP-43的聚集,大多数ALS病例的标志,导致
选择性丢失编码功能性STMN 2的mRNA,STMN 2是一种关键的轴突存活因子。第二,SARM 1的丢失
在小鼠ALS模型中抑制一些神经退行性表型,
TDP-43在这里,我们调查的贡献,这轴突退化途径ALS。我们已经定义了
SARM 1的作用机制,表明它是一类新的NAD切割的创始成员
内切酶SARM 1酶活性通常通过自抑制结构域进行控制。伤害-或疾病-
NMNAT 2和STMN 2的诱导损失使SARM 1失去抑制作用,导致NAD+快速消耗,代谢
灾难和轴突断裂。我们对SARM 1蛋白的结构-功能研究已经确定
具有一系列后果的突变,从促进细胞死亡和轴突生长的组成性活性变体,
失活,转化为具有神经保护作用的显性负性变体。这些发现意味着人类变异可能存在
促进或防止神经退行性变,
遗传变异的研究需要对酶活性进行功能研究。为了支持这一假设,我们发现
ALS患者中的几种罕见SARM 1变体,但对照中没有,具有组成型NAD酶活性,
促进神经元死亡和轴突损失。当这些变异还导致运动功能障碍和瘫痪时,
在小鼠CNS中表达,表明激活SARM 1突变可能有助于ALS发病机制。
在这里,我们建议定义ALS患者,对照组和一般患者的SARM 1变体的功能。
人口这些研究将使我们能够将SARM 1变异体归类为脓毒性促变性,
神经保护或中性。与此同时,我们将剖析变化的组成部分的贡献,
程序性轴突破坏途径对ALS表型的影响,单独和与已知的ALS遗传
风险因素,在从人类诱导多能干细胞(iPSC)分化的运动神经元。最后我们将
研究携带相当于前-
在ALS患者中发现的退行性等位基因,单独和与SOD 1模型组合,基于特定的
病人的基因型我们将尝试通过抑制SARM 1来抑制ALS表型,
已被证实的基因治疗方法和实验性小分子抑制剂。这些研究的结果将
建立SARM 1介导的轴突破坏程序和ALS之间的关系,并建立
基金会开发轴向保护疗法来治疗这种毁灭性的疾病。
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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