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Factors modulating the interaction of huntingtin with lipid membranes: Implications for Huntington's Disease

调节亨廷顿蛋白与脂膜相互作用的因素：对亨廷顿病的影响

基本信息

批准号：
8812396
负责人：
Justin Legleiter
金额：
$ 44.78万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8812396
关键词：
Acetylation Alzheimer&apos s Disease Amino Acids Binding Biological Biological Assay Cessation of life Cholesterol Data Development Disease Functional disorder Ganglioside GM1 Goals Huntington Disease Knowledge Lead Lipid Bilayers Lipids Liquid substance Mass Spectrum Analysis Measurement Measures Mechanics Membrane Membrane Lipids Mission Modeling Modification Molecular Mutation Neurodegenerative Disorders Neurons Parkinson Disease Pathogenesis Pathology Peptides Phosphorylation Play Post-Translational Protein Processing Process Property Proteins Public Health Publishing Reporting Research Role Scanning Scanning Probe Microscopy Series Sphingomyelins Spinocerebellar Ataxias Structure Surface Techniques Testing Therapeutic Therapeutic Intervention Toxic effect Trinucleotide Repeats Vesicle Work base design expectation human Huntingtin protein human disease improved innovation insight macromolecule mutant nanoscale novel therapeutics polyglutamine polyproline prevent protein aggregate prototype public health relevance research study self assembly synthetic construct therapeutic target

项目摘要

DESCRIPTION (provided by applicant): There is a fundamental gap in understanding how small aggregates formed by mutant forms of the huntingtin (htt) protein with expanded polyQ tracts gain toxic biological properties causing Huntington's disease (HD) and, more specifically, how these proteins interact with cellular surfaces comprised of lipids. Continued existence of this gap represents an important problem because these interactions may represent a fundamental step in htt- induced cellular toxicity and understanding of this phenomenon can lead to new targets for therapeutic intervention. The long-term goal of our research is to understand the physicochemical aspects and molecular mechanisms of nanoscale, pathological self-assembly of biological macromolecules that lead to toxicity. The objective in this application is to elucidate the role of lipids on htt misfolding, aggregation, and related toxicity by determinng the impact htt aggregates have on the integrity of cellular and subcellular membranous surfaces. Our central hypothesis is that the binding of mutant htt and its aggregate forms to subcellular surfaces comprised predominately of lipids is a fundamental step associated with toxicity and is facilitated by lipid composition of the membrane and post-translational modifications (PTMs) of htt. This hypothesis is based on preliminary data demonstrating that mutant huntingtin (htt) fragments and synthetic polyQ peptides accumulate on and destabilize model lipid bilayers depending on the availability of specific flanking sequences, such as the firs 17 amino acids of htt or a polyproline domain. The rationale for the proposed work is that detailed knowledge of the aggregation process of mutant htt proteins at lipid membrane interfaces can be expected to ultimately lead to the development of novel therapeutic and neuroprotective targets for HD. Guided by our preliminary studies, this hypothesis will be tested by pursuing two specific aims: 1) Identify lipid components that play a role in the binding of htt o membranes; and 2) Determine how post-translational modification regulate the interaction between htt and lipid membranes. Under the first aim, scanning probe and a variety of vesicle-based assays will be employed to characterize and measure the endogenous interactions occurring between htt and membranes enriched with cholesterol, sphingomyelin, or GM1. Under the second aim, a combination of spectroscopic, mass spectrometry, and scanning probe techniques will be applied to the study of the role of biologically PTMs play in modulating htt/lipd interactions. The proposed research is innovative because it focuses on the impact of physical and mechanical consequences of htt (and its aggregate forms) binding and inserting into lipid membranes that may ultimately lead to cellular dysfunction and death. This contribution is significant because it is expected to provide mechanistic knowledge of htt interaction and aggregation at lipid surfaces, which potentially represents a fundamental step in HD pathology.

描述（由申请人提供）：在理解由突变形式的亨廷顿蛋白（htt）与扩大的多q束形成的小聚集体如何获得导致亨廷顿病（HD）的毒性生物学特性，更具体地说，这些蛋白质如何与由脂质组成的细胞表面相互作用方面存在根本空白。这种差距的持续存在代表了一个重要的问题，因为这些相互作用可能代表了高温诱导的细胞毒性的一个基本步骤，对这一现象的理解可以为治疗干预提供新的靶点。我们研究的长期目标是了解导致毒性的生物大分子的纳米级病理自组装的物理化学方面和分子机制。这个应用程序的目标

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ion Mobility Spectrometry-Hydrogen Deuterium Exchange Mass Spectrometry of Anions: Part 2. Assessing Charge Site Location and Isotope Scrambling.

DOI：
10.1007/s13361-015-1304-x
发表时间：
2016-03
期刊：
Journal of the American Society for Mass Spectrometry
影响因子：
3.2
作者：
Khakinejad M;Kondalaji SG;Donohoe GC;Valentine SJ
通讯作者：
Valentine SJ

Sphingomyelin and GM1 Influence Huntingtin Binding to, Disruption of, and Aggregation on Lipid Membranes.

DOI：
10.1021/acsomega.7b01472
发表时间：
2018-01-31
期刊：
ACS omega
影响因子：
4.1
作者：
Chaibva M;Gao X;Jain P;Campbell WA 4th;Frey SL;Legleiter J
通讯作者：
Legleiter J

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease.

DOI：
10.1021/acs.biochem.6b00936
发表时间：
2017-03-07
期刊：
Biochemistry
影响因子：
2.9
作者：
Adegbuyiro A;Sedighi F;Pilkington AW 4th;Groover S;Legleiter J
通讯作者：
Legleiter J

Mitochondrial membranes modify mutant huntingtin aggregation.

DOI：
10.1016/j.bbamem.2021.183663
发表时间：
2021-10-01
期刊：
Biochimica et biophysica acta. Biomembranes
影响因子：
0
作者：
Adegbuyiro A;Sedighi F;Jain P;Pinti MV;Siriwardhana C;Hollander JM;Legleiter J
通讯作者：
Legleiter J

The emerging role of the first 17 amino acids of huntingtin in Huntington's disease.