Cysteine-string Protein and Neurodegeneration

半胱氨酸串蛋白与神经变性

基本信息

批准号：
10039978
负责人：
KONRAD ERNST ZINSMAIER
金额：
$ 42.21万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10039978
关键词：
Affinity Alleles Animal Model Attenuated Autopsy Axon Binding Sites Biochemical Brain Cessation of life Cultured Cells Cysteine Defect Dependence Dimerization Disease Drosophila genus Drug Targeting Endosomes Estrogen receptor positive Etiology Event Failure Fibroblasts Fostering Future Gene Dosage Genes Golgi Apparatus Human Impairment Induced Mutation Inherited Lead Life Expectancy Link Lysosomal Storage Diseases Mediating Membrane Modeling Molecular Multivesicular Body Mus Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neuronal Ceroid-Lipofuscinosis Neurons PC12 Cells Pathologic Pathology Pathway interactions Patients Phenotype Property Protein Secretion Proteins Resistance Role Route Signal Transduction Site Sorting - Cell Movement Spielmeyer-Vogt Disease Synapses Synaptic Vesicles Testing Therapeutic Therapeutic Intervention Toxic effect alpha synuclein brain cell cysteine string protein extracellular vesicles fly gain of function mutation genetic approach insight misfolded protein mutant neuronal cell body novel palmitoylation premature prevent protein TDP-43 protein aggregation synaptic function therapeutic development trafficking

Affinity Alleles Animal Model Attenuated Autopsy Axon Binding Sites Biochemical Brain Cessation of life Cultured Cells Cysteine Defect Dependence Dimerization Disease Drosophila genus Drug Targeting Endosomes Estrogen receptor positive Etiology Event Failure Fibroblasts Fostering Future Gene Dosage Genes Golgi Apparatus Human Impairment Induced Mutation Inherited Lead Life Expectancy Link Lysosomal Storage Diseases Mediating Membrane Modeling Molecular Multivesicular Body Mus Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neuronal Ceroid-Lipofuscinosis Neurons PC12 Cells Pathologic Pathology Pathway interactions Patients Phenotype Property Protein Secretion Proteins Resistance Role Route Signal Transduction Site Sorting - Cell Movement Spielmeyer-Vogt Disease Synapses Synaptic Vesicles Testing Therapeutic Therapeutic Intervention Toxic effect alpha synuclein brain cell cysteine string protein extracellular vesicles fly gain of function mutation genetic approach insight misfolded protein mutant neuronal cell body novel palmitoylation premature prevent protein TDP-43 protein aggregation synaptic function therapeutic development trafficking

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项目摘要

The necessity of understanding causes of neurodegenerative diseases and developing potential treatments is increasing as life expectancy is extending. Neuronal ceroid lipofuscinoses (NCLs; also known as Batten disease) comprise a group of 14 monogenic neurodegenerative diseases with lysosomal pathology (CLN1-14). NCLs are typically due to recessive mutations in genes that mediate lysosomal function or ER-lysosomal trafficking with one atypical exception: the dominantly inherited NCL CLN4, which is caused by mutations in the synaptic vesicle (SV) protein CSPα. Normally, CSPα is critical to maintain synaptic function and prevent activity-dependent neurodegeneration. It also mediates the clearance of aggregating proteins like TDP-43 or α-synuclein by unconventional secretion pathways. Little is known about CLN4 disease etiology besides biochemical evidence that CLN4-causing mutations induce the formation of ubiquitinated CSPα oligomers/aggregates. Whether and how the oligomeric or monomeric protein causes lysosomal failure, neurodegeneration, and premature death remains enigmatic. We have established the first animal models of CLN4 by expressing disease-causing human CSPα (hCSPα) or fly CSP (dCSP) in Drosophila neurons. Both models recapitulate the biochemical pathology of CLN4 post-mortem brains. Further analysis revealed a novel link between CLN4 mutant CSP and prelysosomal failure. Unexpectedly, we also found that the dominant CLN4 alleles act as hypermorphic gain of function mutations inducing the oligomerization of CSP, prelysosomal failure, neurodegeneration, and lethality. We suggest that hypermorphic CLN4 mutations increase the affinity for some or one of CSP’s protein interaction causing disease. Next to an exaggerated dimerization of CSP leading to oligomerization, CLN4 mutations increase interactions of CSP with the synaptically localized palmitoyl-transferase Hip14 that could lead to prelysosomal failure. Finally, increased interactions of CSP with Hsc70 on endosomes destined to form multivesicular bodies may interfere with their processing, sorting and/or trafficking. We propose to test these possibilities by genetic approaches to better understand both the mechanisms underlying CSP’s normal neuroprotective role, and the mechanisms underlying the hypermorphic CLN4 mutations causing protein aggregation, lysosomal failure, neurodegeneration, and premature death. Uncovering mechanisms underlying CLN4 may inform the future development of therapeutic interventions. In addition, a better understanding of CSP’s neuroprotective role is important for various other neurodegenerative diseases that may be attenuated by CSP’s clearance of misfolded proteins.

理解神经退行性疾病并发展潜力的必要原因随着预期寿命的延长，治疗正在增加。神经元粘膜脂肪糖苷（NCLS；也是被称为巴顿疾病）建立一组14种单基因神经退行性疾病溶酶体病理学（CLN1-14）。 NCL通常是由于介导的基因隐性突变溶酶体功能或ER溶菌体运输，一个非典型例外：主要遗传的NCL Cln4是由突触囊泡（SV）蛋白CSPα突变引起的。通常，CSPα至关重要维持突触功能并防止活动依赖性神经变性。它也介导通过非常规分泌途径清除聚集的蛋白质（如TDP-43或α-突触核蛋白）。除了生化证据表明CLN4引起CLN4疾病病因之外，对CLN4疾病的病因知之甚少突变诱导泛素化的CSPα低聚物/聚集体的形成。是否以及如何以及如何寡聚或单体蛋白会导致溶酶体衰竭，神经退行性和过早死亡保持神秘。我们通过表达引起疾病的第一个CLN4动物模型果蝇神经元中的人CSPα（HCSPα）或Fly CSP（DCSP）。两种模型都概括了 CLN4后大脑的生化病理学。进一步的分析揭示了一种新的联系 CLN4突变体CSP和prelysosomal衰竭。出乎意料的是，我们还发现主要的CLN4 等位基因充当功能突变的超态增益，诱导CSP的低聚失败，神经退行性和致死性。我们建议超态CLN4突变增加了对CSP蛋白的某些或一种的亲和力相互作用引起疾病。在CSP的夸大二聚体旁边导致低聚， CLN4突变增加了CSP与突触局部棕榈酰转移酶HIP14的相互作用这可能会导致严重的染色体衰竭。最后，增加了CSP与内体上HSC70的相互作用注定要形成多种机构可能会干扰其处理，分类和/或贩运。我们提出通过遗传方法测试这些可能性的建议，以更好地了解这两种机制 CSP的基本正常神经保护作用以及超态CLN4的基础机制引起蛋白质聚集，溶酶体衰竭，神经变性和过早死亡的突变。发现CLN4的基础机制可能会告知治疗的未来发展干预措施。此外，更好地了解CSP的神经保护作用对于各种 CSP清除错误折叠蛋白的其他神经退行性疾病可能会减弱。