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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

基本信息

批准号：
10539942
负责人：
Joseph R Mazzulli
金额：
$ 61.85万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10539942
关键词：
Biogenesis Biological Biology Brain Cell Death Cell physiology Cells Clinic Data Dementia with Lewy Bodies Disease Documentation Endoplasmic Reticulum Enhancers Failure Foundations Functional disorder Funding Genetic study Glucose Glycolipids Glycosphingolipids Golgi Apparatus Hexosamines Human Hydrolase In Vitro Inclusion Bodies Induced pluripotent stem cell derived neurons Knowledge Lead Lewy Bodies Link Lysosomes Membrane Fusion Methods Modeling Mutation Nerve Degeneration Nervous system structure Neurons Parkinson Disease Parkinson&apos s Dementia Pathogenesis Pathogenicity Pathology Pathway interactions Patients Phenotype Play Process Proteins Quality Control Role SNAP receptor Solubility Structure System Testing Toxic effect Transducers Work age related alpha synuclein base clinical development efficacy testing genetic risk factor genetic variant glucosylceramidase glycosylation improved in vivo induced pluripotent stem cell link protein loss of function loss of function mutation misfolded protein mouse model neurotoxicity new therapeutic target novel novel therapeutic intervention prevent protein aggregation protein folding protein transport proteostasis response sensor small molecule sound synucleinopathy therapy development trafficking

项目摘要

Abstract The aggregation of a-Synuclein (a-syn) into insoluble fibrils plays a key role in the pathogenesis of Dementia with Lewy bodies (DLB), Parkinson’s disease (PD) and other synucleinopathies. Despite the documentation of a-synuclein as a component of Lewy body inclusions for over 25 years, there remains a significant knowledge gap in the mechanisms that causally link protein aggregates to neurodegeneration. Recent genetic studies have implicated the lysosomal degradation system into the pathogenesis of DLB and PD. Among the strongest genetic risk factors are loss-of-function mutations lysosomal β-glucocerebrosidase (GCase) encoded by GBA1, indicating that compromised lysosomal function may play a direct role in neurodegeneration. During our previous funding period, we found that a-syn aggregates are initiated inside lysosomes by interacting with glycosphingolipid substrates that accumulate upon loss of GCase. Once formed, these aggregates perturb multiple, essential branches of the proteostasis pathway, including the folding in the endoplasmic reticulum (ER) and post-ER trafficking at the cis-Golgi. This further augments a-syn aggregation, creating a self-propagating pathogenic cycle. The previous funding period uncovered novel mechanisms and biological targets that enhance the trafficking of hydrolases and lysosomal function. Here, we will build on our previous work to examine how a- syn aggregates perturb protein folding in the ER, N-linked glycosylation in the ER, and the downstream effect on lysosomal function. We will develop novel molecules to restore these key proteostasis pathways. Our studies will employ a combination of patient-derived PD iPSC-neuron cultures, synucleinopathy mouse models, and human brain. We previously found that a-syn accumulation in PD patient neurons induced ER fragmentation and concealed the cell’s ability to recognize misfolded proteins in the ER, resulting in aggregation of immature GCase. Since misfolded proteins in the ER are usually recognized by the unfolded protein response (UPR), in aim 1, we will examine the link between the UPR, GCase solubility, and trafficking to the lysosome. We will determine if triggering the UPR in PD can restore lysosomal function and reduce a-syn. In aim 2, we will test the hypothesis that reduced glucose flux and protein N-glycosylation of GCase and other hydrolases contributes to lysosomal depletion and dysfunction in PD. In aim 3, we will build upon our prior studies, which showed that lysosomal function can be rescued by enhancing the SNARE protein ykt6. We will test novel small molecule activators of the ykt6-lysosomal biogenesis pathway in vitro and in vivo. By studying basic biology mechanisms of protein trafficking, we have a unique opportunity to link essential cellular proteostasis pathways to disease pathogenesis. Our studies may impact the field by discovering novel pathogenic mechanisms, identifying new biological targets, and further develop therapies to enhance lysosomal biogenesis to restore proteostasis in PD and DLB.

摘要