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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：
Joseph R Mazzulli
金额：
$ 19.75万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
https://reporter.nih.gov/project-details/9788110
关键词：
Brain Brain Diseases Cell Death Cell Line Cell model Cells Clinic Clinical Complex Data Degradation Pathway Disease Endoplasmic Reticulum Enzymes Etiology Farnesyl Transferase Inhibitor Foundations Functional disorder Future Genetic study Genotype Glucosylceramides Goals Golgi Apparatus Hydrolase Idiopathic Parkinson Disease Lead Lewy Bodies Link Lysosomes Measures Mediating Membrane Fusion Methods Midbrain structure Modeling Molecular Chaperones Molecular Conformation Movement Disorders Nerve Degeneration Nervous system structure Neurites Neurodegenerative Disorders Neurons Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Pharmacology Phenotype Play Point Mutation Process Protein Farnesylation Proteins Regulation Role SNAP receptor SNCA gene Safety Therapeutic Therapeutic Agents Toxic effect Translating Variant Vesicle Work age related neurodegeneration alpha synuclein cancer therapy disorder risk dopaminergic neuron druggable target farnesylation genetic risk factor genome wide association study genome-wide glucosylceramidase improved in vitro Assay in vivo induced pluripotent stem cell insight loss of function mutation mutant neuron loss new therapeutic target novel novel therapeutics overexpression protein aggregate protein degradation protein transport proteostasis receptor receptor binding small molecule small molecule inhibitor soluble NSF attachment protein sound synucleinopathy therapeutic target trafficking

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