Mechanistic studies and therapeutics for ALS-FTD linked to UBQLN2 mutations
与 UBQLN2 突变相关的 ALS-FTD 的机制研究和治疗
基本信息
- 批准号:10063576
- 负责人:
- 金额:$ 50.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-01-15 至 2022-01-31
- 项目状态:已结题
- 来源:
- 关键词:ALS patientsAblationAffectAmyotrophic Lateral SclerosisAnimal Disease ModelsAnimalsAutophagocytosisAutophagosomeBacterial Artificial ChromosomesBehavioralBindingBinding ProteinsBiochemicalBiological AssayBrainCell physiologyCellsCognitive deficitsDataDefectDevelopmentFrontotemporal DementiaFunctional disorderGenesGeneticGoalsHumanImmunofluorescence ImmunologicImmunoprecipitationLinkLysosomesMapsMediatingMemory impairmentMissense MutationMotor Neuron DiseaseMotor NeuronsMusMutationNerve DegenerationNeurodegenerative DisordersNeuronsOutcomePathogenesisPathologicPathway interactionsPlayProteinsRegulationRoleSiteSpinal CordStainsSymptomsSystemTBK1 geneTestingTherapeuticTherapeutic StudiesTransgenic MiceTransgenic OrganismsUBQLN1 geneUbiquitinWild Type MouseWorkamyotrophic lateral sclerosis therapydisease-causing mutationend stage diseaseexperimental studyfrontotemporal lobar dementia-amyotrophic lateral sclerosisgenetic manipulationhuman diseaseinsightmisfolded proteinmouse modelmulticatalytic endopeptidase complexmutantneuron lossoverexpressionpromoterprotein degradationprotein functionreceptor bindingtreatment strategyubiquilin
项目摘要
Summary
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder associated with loss
of upper and lower motor neurons. Some ALS patients also develop frontotemporal dementia (FTD). Genetic
findings have linked mutations in different genes to the range of symptoms seen in ALS. This proposal focuses
on UBQLN2, missense mutations in which cause dominant inheritance of ALS-FTD. UBQLN2 is one of four
ubiquilin (UBQLN) proteins found in humans. UBQLN proteins function to clear misfolded proteins from cells
through the proteasome and autophagy pathways. This function could be important in neurodegenerative
diseases, where a build up of misfolded proteins is frequently seen. Therefore, understanding how UBQLN
proteins function and dysfunction has broad implications for neurodegenerative diseases. Animal models of the
disease are useful for understanding the mechanisms of pathogenesis and for therapeutic studies. Toward
such a goal, we generated and characterized transgenic mice carrying Thy1.2 promoter-driven expression of
human UBQLN2 proteins encoding either the wild type (WT) or the P497S or P506S mutants that cause ALS-
FTD. Mouse lines carrying each of the mutations were found to develop motor neuron disease and cognitive
deficits, mimicking the human disease, whereas the WT mice were devoid of motor neuron disease.
Immunoblots of spinal cord proteins revealed a dramatic reduction in TBK1 levels in animals with end-stage
disease in both the mutant UBQLN2 mouse lines compared to non-transgenic animals. The reduction could be
significant because haploinsufficiency of TBK1 expression caused by TBK1 mutations were recently linked to
ALS-FTD. Prompted by these relationships, we examined whether TBK1 binds with UBQLN2. Double
immunofluorescence staining indicated TBK1 and UBQLN colocalize in cells in autophagosomes. Furthermore,
by both immunoprecipitation and GST-pulldown assays we found WT UBQLN2 binds TBK1, but the ALS
UBQLN2 mutant proteins bind more TBK1. We hypothesize that the increased binding with UBQLN2 mutants
alters one or both of the protein's functions. Accordingly, we propose experiments in Aim 1 to study the
functional significance of the interaction, and how mutations in UBQLN2 affect this interaction especially with
regard to the function of the proteins in autophagy, which we found is disturbed in our mutant UBQLN2 mouse
lines. In Aim 2, we will determine whether transgenic overexpression of TBK1, in an effort to restore its levels
in our UBQLN2 mice, will extend survival and delay ALS-FTD symptoms. In Aim 3, will investigate the exciting
possibility, supported by our preliminary studies in double transgenic mice, that overexpression of UBQLN1 in
our mtUBQLN2 lines will delay ALS-FTD symptoms. The outcome of this work is likely to be important both in
terms of its implications for our understanding of the underlying mechanisms involved in ALS-FTD
pathogenesis and because it could reveal whether modulation of TBK1 and UBQLN1 levels can serve as
tractable therapeutic strategies to treat ALS-FTD.
摘要
肌萎缩侧索硬化症(ALS)是一种进行性和致命性的神经退行性疾病,与丢失有关
上运动神经元和下运动神经元。一些肌萎缩侧索硬化症患者还会患上额颞叶痴呆(FTD)。遗传
研究发现,不同基因的突变与肌萎缩侧索硬化症的症状范围有关。这项提案将重点放在
在UBQLN2上,导致ALS-FTD显性遗传的错义突变。UBQLN2是四个
人类中发现的泛素(UBQLN)蛋白。UBQLN蛋白清除细胞中错误折叠蛋白的功能
通过蛋白酶体和自噬途径。这一功能在神经退行性变中可能很重要。
疾病,其中错误折叠的蛋白质堆积是常见的。因此,了解UBQLN如何
蛋白质的功能和功能障碍对神经退行性疾病具有广泛的意义。大鼠的动物模型
疾病对于理解发病机制和治疗研究是有用的。冲向
为了达到这一目标,我们构建并鉴定了携带Thy1.2启动子驱动表达的转基因小鼠
人类编码野生型(WT)或导致ALS的P497S或P506S突变体的UBQLN2蛋白-
FTD。携带每一种突变的小鼠品系被发现会患上运动神经元疾病和认知
缺陷,模仿人类疾病,而WT小鼠没有运动神经元疾病。
脊髓蛋白免疫印迹显示终末期动物的TBK1水平显著降低
与非转基因动物相比,这两个突变的UBQLN2小鼠品系中的疾病。减幅可能是
重要的是因为最近发现由TBK1突变引起的单倍体表达不足与
ALS-FTD。在这些关系的提示下,我们检查了TBK1是否与UBQLN2结合。双倍
免疫荧光染色显示,TBK1和UBQLN共存于自噬小体的细胞内。此外,
通过免疫沉淀和GST-Pull-Down实验,我们发现WT UBQLN2与TBK1结合,但ALS
UBQLN2突变蛋白与更多的TBK1结合。我们推测,与UBQLN2突变体结合的增加
改变蛋白质的一种或两种功能。因此,我们建议在目标1中进行实验,以研究
相互作用的功能意义,以及UBQLN2的突变如何影响这种相互作用,特别是与
关于自噬中蛋白质的功能,我们在突变的UBQLN2小鼠中发现这一功能受到干扰
台词。在目标2中,我们将确定是否转基因过表达了TBK1,以努力恢复其水平
在我们的UBQLN2小鼠中,将延长存活时间并延缓ALS-FTD症状。在目标3中,将调查令人兴奋的
我们在双转基因小鼠中的初步研究支持了UBQLN1在
我们的mtUBQLN2线将延缓ALS-FTD症状。这项工作的结果可能在两个方面都很重要
它对我们理解ALS-FTD潜在机制的影响
发病机制,因为它可以揭示TBK1和UBQLN1水平的调节是否可以作为
治疗ALS-FTD的易处理的治疗策略。
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Serpin neuropathology in the P497S UBQLN2 mouse model of ALS/FTD.
- DOI:10.1111/bpa.12948
- 发表时间:2021-09
- 期刊:
- 影响因子:0
- 作者:Higgins NR;Greenslade JE;Wu JJ;Miranda E;Galliciotti G;Monteiro MJ
- 通讯作者:Monteiro MJ
Overexpression of UBQLN1 reduces neuropathology in the P497S UBQLN2 mouse model of ALS/FTD.
- DOI:10.1186/s40478-020-01039-9
- 发表时间:2020-10-07
- 期刊:
- 影响因子:7.1
- 作者:Wang S;Tatman M;Monteiro MJ
- 通讯作者:Monteiro MJ
UBQLN proteins in health and disease with a focus on UBQLN2 in ALS/FTD.
健康和疾病中的UBQLN蛋白质,重点是ALS/FTD中的UBQLN2。
- DOI:10.1111/febs.16129
- 发表时间:2022-10
- 期刊:
- 影响因子:0
- 作者:Lin BC;Higgins NR;Phung TH;Monteiro MJ
- 通讯作者:Monteiro MJ
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Mervyn J Monteiro其他文献
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{{ truncateString('Mervyn J Monteiro', 18)}}的其他基金
Deciphering the role of ER stress in ALS pathogenesis caused by UBQLN2 mutations
解读 ER 应激在 UBQLN2 突变引起的 ALS 发病机制中的作用
- 批准号:
10207794 - 财政年份:2017
- 资助金额:
$ 50.44万 - 项目类别:
Deciphering the role of ER stress in ALS pathogenesis caused by UBQLN2 mutations
解读 ER 应激在 UBQLN2 突变引起的 ALS 发病机制中的作用
- 批准号:
9318653 - 财政年份:2017
- 资助金额:
$ 50.44万 - 项目类别:
Quality control of APP cleavage by RING-finger ubiquitin ligases
通过环指泛素连接酶进行 APP 切割的质量控制
- 批准号:
9308437 - 财政年份:2017
- 资助金额:
$ 50.44万 - 项目类别:
Mechanistic studies and therapeutics for ALS/FTD linked to UBQLN2 mutations
与 UBQLN2 突变相关的 ALS/FTD 的机制研究和治疗
- 批准号:
10373433 - 财政年份:2017
- 资助金额:
$ 50.44万 - 项目类别:
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生成监测神经元 ERAD 的小鼠模型
- 批准号:
9331759 - 财政年份:2016
- 资助金额:
$ 50.44万 - 项目类别:
Generation of a mouse model to monitor ERAD in neurons
生成监测神经元 ERAD 的小鼠模型
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9251591 - 财政年份:2016
- 资助金额:
$ 50.44万 - 项目类别:
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