Exploring the role of protein farnesylation in the regulation of SNARE protein ykt6 in synucleinopathy models
探索蛋白法尼基化在突触核蛋白病模型中 SNARE 蛋白 ykt6 调节中的作用
基本信息
- 批准号:9788110
- 负责人:
- 金额:$ 19.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-30 至 2021-02-28
- 项目状态:已结题
- 来源:
- 关键词:BrainBrain DiseasesCell DeathCell LineCell modelCellsClinicClinicalComplexDataDegradation PathwayDiseaseEndoplasmic ReticulumEnzymesEtiologyFarnesyl Transferase InhibitorFoundationsFunctional disorderFutureGenetic studyGenotypeGlucosylceramidesGoalsGolgi ApparatusHydrolaseIdiopathic Parkinson DiseaseLeadLewy BodiesLinkLysosomesMeasuresMediatingMembrane FusionMethodsMidbrain structureModelingMolecular ChaperonesMolecular ConformationMovement DisordersNerve DegenerationNervous system structureNeuritesNeurodegenerative DisordersNeuronsParkinson DiseasePathogenesisPathogenicityPathologicPathway interactionsPatientsPharmacologyPhenotypePlayPoint MutationProcessProtein FarnesylationProteinsRegulationRoleSNAP receptorSNCA geneSafetyTherapeuticTherapeutic AgentsToxic effectTranslatingVariantVesicleWorkage related neurodegenerationalpha synucleincancer therapydisorder riskdopaminergic neurondruggable targetfarnesylationgenetic risk factorgenome wide association studygenome-wideglucosylceramidaseimprovedin vitro Assayin vivoinduced pluripotent stem cellinsightloss of function mutationmutantneuron lossnew therapeutic targetnovelnovel therapeuticsoverexpressionprotein aggregateprotein degradationprotein transportproteostasisreceptorreceptor bindingsmall moleculesmall molecule inhibitorsoluble NSF attachment proteinsoundsynucleinopathytherapeutic targettrafficking
项目摘要
Abstract
Synucleinopathies, such as Parkinson's disease (PD), are a group of incurable neurodegenerative diseases
characterized by the accumulation of aggregated alpha-synuclein (a-syn). Disturbances in protein trafficking and
cellular degradation pathways, such as lysosomes, have been implicated in the pathogenesis of these disorders.
The strongest genetic risk factors for PD are loss-of-function mutations in lysosomal glucocerebrosidase
(GCase), that degrades glucosylceramide (GluCer). Our previous work showed that loss of GCase activity and
GluCer accumulation directly induces a-syn aggregation and cell death in neurons. This indicates that lysosomal
dysfunction plays an important role in PD pathogenesis, and that enhancing lysosomal function may reduce a-
syn aggregation. We also showed that a-syn, when aggregated at the cell body of neurons, inhibits the trafficking
of lysosomal hydrolases between the endoplasmic reticulum (ER) and the Golgi, thereby reducing lysosomal
function. Therefore, methods to enhance ER-Golgi trafficking may improve lysosomal hydrolase targeting and
function, and enhance the clearance of pathological a-syn aggregates. However no therapeutic targets exist that
are capable of enhancing trafficking or lysosomal activity. We propose to explore the mechanism of a potential
novel therapeutic target called ykt6 that functions as a Soluble NSF Attachment protein REceptor (SNARE) to
enhance protein trafficking between the ER and the Golgi, therefore improving the maturation of lysosomal
enzymes and hydrolase activity. Previous work has shown that cognate SNARE binding of ykt6 is regulated by
farnesylation, and we will examine how farnesylation of ykt6 influences its ability to control ER-Golgi trafficking
using PD patient-derived neurons from induced pluripotent stem cell (iPSC) models and isogenic corrected
controls. Preliminary data indicate that inhibiting the farnesylation of ykt6 enhances the trafficking of lysosomal
hydrolases and improves lysosomal function. Furthermore, pharmacological inhibition of farnesyltransferase
using a brain-penetrant, clinically validated small-molecule inhibitor can reduce pathological, insoluble a-syn in
cell lines in a ykt6-dependent manner. We propose to examine how the farnesyl-mediated regulatory mechanism
of ykt6 function is related to its ability to enhance lysosomal function and reduce pathological a-syn. As these
studies are exploratory, they are aimed to assess the future potential of ykt6 as a therapeutic target for the
synucleinopathies by focusing on the mechanism that regulates its ER-Golgi trafficking activity. We expect these
studies to lead to novel hypothesis for regulation of ER-Golgi trafficking and lysosomal activity, and possibly
other vesicular trafficking pathways in the cell, that may be examined in future proposals. There are currently no
known methods to enhance hydrolase trafficking and lysosomal function, and our studies may help to validate
ykt6 as a druggable target to enhance these processes and reduce pathological forms of a-syn. Our studies may
be rapidly translated into therapies since farnesyltransferase inhibitors are well-developed in the clinic as cancer
therapies, leading to the possibility of repurposing these agents for the treatment of PD.
摘要
突触核蛋白病,如帕金森病(PD),是一组无法治愈的神经退行性疾病
其特征在于聚集的α-突触核蛋白(α-syn)的积累。蛋白质运输的干扰,
细胞降解途径如溶酶体与这些疾病的发病机制有关。
PD最强的遗传风险因素是溶酶体葡萄糖脑苷脂酶的功能缺失突变
(GCase),其降解葡糖神经酰胺(GluCer)。我们以前的工作表明,GCase活性的丧失和
GluCer积累直接诱导神经元中的α-syn聚集和细胞死亡。这表明溶酶体
功能障碍在PD发病机制中起着重要作用,增强溶酶体功能可能会减少
同步聚合。我们还发现,当a-syn聚集在神经元的细胞体上时,
内质网(ER)和高尔基体之间的溶酶体水解酶,从而减少溶酶体
功能因此,增强ER-高尔基体运输的方法可以改善溶酶体水解酶靶向,
功能,并增强病理性a-syn聚集体的清除。然而,不存在治疗靶点,
能够增强运输或溶酶体活性。我们建议探索一种潜在的
称为ykt 6的新型治疗靶点,其作为可溶性NSF附着蛋白受体(SNARE)发挥作用,
增强内质网和高尔基体之间的蛋白质运输,从而改善溶酶体的成熟
酶和水解酶活性。先前的工作表明,ykt 6的同源SNARE结合受以下因素调节:
法尼基化,我们将研究如何法尼基化的ykt 6影响其能力,以控制ER-高尔基体运输
使用来自诱导多能干细胞(iPSC)模型和等基因校正的PD患者来源的神经元
对照初步数据表明,抑制ykt 6的法尼基化增强了溶酶体的运输。
水解酶并改善溶酶体功能。此外,法尼基转移酶的药理学抑制
使用脑渗透剂,临床验证的小分子抑制剂可以减少病理性的,不溶性的α-syn,
以YKT 6依赖的方式对细胞系进行抑制。我们建议研究法尼基介导的调节机制
YKT 6功能的降低与其增强溶酶体功能和减少病理性α-syn的能力有关。因为这些
研究是探索性的,它们旨在评估ykt 6作为治疗靶点的未来潜力。
突触核蛋白病的机制,重点是调节其ER-高尔基体运输活动。我们预计这些
研究,导致新的假说,调节ER-高尔基体运输和溶酶体活性,并可能
细胞中的其他囊泡运输途径,可能会在未来的提案中进行审查。目前没有
已知的方法来增强水解酶运输和溶酶体功能,我们的研究可能有助于验证
YKT 6作为可药物化的靶点,以增强这些过程并减少病理形式的α-syn。我们的研究可能
由于法尼基转移酶抑制剂在临床上作为癌症的治疗药物得到了很好的发展,
治疗,导致重新利用这些药物治疗PD的可能性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Joseph R Mazzulli其他文献
Joseph R Mazzulli的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Joseph R Mazzulli', 18)}}的其他基金
Exploring the Pathogenic Mechanisms of Batten's disease MFSD8 mutations using patient iPSC derived neurons.
使用患者 iPSC 衍生的神经元探索巴顿病 MFSD8 突变的致病机制。
- 批准号:
10467764 - 财政年份:2022
- 资助金额:
$ 19.75万 - 项目类别:
Exploring the Pathogenic Mechanisms of Batten's disease MFSD8 mutations using patient iPSC derived neurons.
使用患者 iPSC 衍生的神经元探索巴顿病 MFSD8 突变的致病机制。
- 批准号:
10581666 - 财政年份:2022
- 资助金额:
$ 19.75万 - 项目类别:
Examining the role of phosphatidylethanolamine and autophagic disruption in Lewy Body Dementias and Parkinson's disease
检查磷脂酰乙醇胺和自噬破坏在路易体痴呆和帕金森病中的作用
- 批准号:
10419671 - 财政年份:2021
- 资助金额:
$ 19.75万 - 项目类别:
Mechanisms of gene regulation and RNA processing in synucleinopathies
突触核蛋白病中的基因调控和 RNA 加工机制
- 批准号:
10650320 - 财政年份:2020
- 资助金额:
$ 19.75万 - 项目类别:
Mechanisms of gene regulation and RNA processing in synucleinopathies
突触核蛋白病中的基因调控和 RNA 加工机制
- 批准号:
10194629 - 财政年份:2020
- 资助金额:
$ 19.75万 - 项目类别:
Mechanisms of gene regulation and RNA processing in synucleinopathies
突触核蛋白病中的基因调控和 RNA 加工机制
- 批准号:
10447768 - 财政年份:2020
- 资助金额:
$ 19.75万 - 项目类别:
The role of a-synuclein accumulation in lysosomal hydrolase trafficking and function
α-突触核蛋白积累在溶酶体水解酶运输和功能中的作用
- 批准号:
9751407 - 财政年份:2015
- 资助金额:
$ 19.75万 - 项目类别:
The role of a-synuclein accumulation in lysosomal hydrolase trafficking and function
α-突触核蛋白积累在溶酶体水解酶运输和功能中的作用
- 批准号:
10659253 - 财政年份:2015
- 资助金额:
$ 19.75万 - 项目类别:
The role of a-synuclein accumulation in lysosomal hydrolase trafficking and function
α-突触核蛋白积累在溶酶体水解酶运输和功能中的作用
- 批准号:
10539942 - 财政年份:2015
- 资助金额:
$ 19.75万 - 项目类别:
The role of a-synuclein accumulation in lysosomal hydrolase trafficking and function
α-突触核蛋白积累在溶酶体水解酶运输和功能中的作用
- 批准号:
8943319 - 财政年份:2015
- 资助金额:
$ 19.75万 - 项目类别:
相似海外基金
Illuminating Brain Diseases Using Smart Multiread-out MRI
使用智能多重读出 MRI 阐明脑部疾病
- 批准号:
MR/X034046/1 - 财政年份:2024
- 资助金额:
$ 19.75万 - 项目类别:
Fellowship
Understanding mechanisms of memory engram updating following memory retrieval and improvement of brain diseases by targeting memory updating
了解记忆检索后记忆印迹更新的机制以及通过靶向记忆更新改善脑部疾病
- 批准号:
22H00358 - 财政年份:2022
- 资助金额:
$ 19.75万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
LEAP-HI: Tackling Brain Diseases with Mechanics: A Data-Driven Approach to Merge Advanced Neuroimaging and Multi-Physics Modeling
LEAP-HI:用力学解决脑部疾病:一种融合先进神经成像和多物理场建模的数据驱动方法
- 批准号:
2227232 - 财政年份:2022
- 资助金额:
$ 19.75万 - 项目类别:
Standard Grant
Engineering Human Brain Neurovascular Niche for Modeling Brain Diseases
工程人脑神经血管生态位以模拟脑疾病
- 批准号:
10478162 - 财政年份:2021
- 资助金额:
$ 19.75万 - 项目类别:
I-Corps: Drug delivery systems for treating degenerative brain diseases
I-Corps:治疗退行性脑疾病的药物输送系统
- 批准号:
2135052 - 财政年份:2021
- 资助金额:
$ 19.75万 - 项目类别:
Standard Grant
Engineered AAV vectors for combinatorial treatment of rare genetic brain diseases
用于罕见遗传性脑部疾病组合治疗的工程 AAV 载体
- 批准号:
10414342 - 财政年份:2021
- 资助金额:
$ 19.75万 - 项目类别:
Engineering Human Brain Neurovascular Niche for Modeling Brain Diseases
工程人脑神经血管生态位以模拟脑疾病
- 批准号:
10303483 - 财政年份:2021
- 资助金额:
$ 19.75万 - 项目类别:
Evaluation for metabolic brain diseases using cerebral oxygen metabolism imaging
利用脑氧代谢成像评估代谢性脑疾病
- 批准号:
20K08136 - 财政年份:2020
- 资助金额:
$ 19.75万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
LEAP-HI: Tackling Brain Diseases with Mechanics: A Data-Driven Approach to Merge Advanced Neuroimaging and Multi-Physics Modeling
LEAP-HI:用力学解决脑部疾病:一种融合先进神经成像和多物理场建模的数据驱动方法
- 批准号:
1953323 - 财政年份:2020
- 资助金额:
$ 19.75万 - 项目类别:
Standard Grant
Medialising Brain Diseases: Interactions between Research and Mass Media
治疗脑部疾病:研究与大众媒体之间的相互作用
- 批准号:
411038189 - 财政年份:2019
- 资助金额:
$ 19.75万 - 项目类别:
Research Grants