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
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)
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Joseph R Mazzulli其他文献
Joseph R Mazzulli的其他文献
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{{ 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:
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