Biophysical determination of the underlying cause of alpha-Syn oligomer toxicity.
α-Syn 寡聚物毒性根本原因的生物物理测定。
基本信息
- 批准号:10803124
- 负责人:
- 金额:$ 20万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-15 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAreaBiophysicsBrainCorpus striatum structureDevelopmentGoalsIndividualLabelLinkLipidsMembraneMidbrain structureMusNeurodegenerative DisordersNeuronsParkinson DiseasePathologyPersonsPlasmaProteinsRegulationSecondary Protein StructureStructureSynaptic VesiclesToxic effectWorkalpha synucleindopaminergic neuronimaging approachinnovationlipid metabolismnervous system disordertrafficking
项目摘要
ABSTRACT
Parkinson disease (PD) is the second most common neurodegenerative disease that
affects nearly 5 millions of people around the world. PD is associated with intracellular
aggregation of α-synuclein (α-Syn), a small protein that is involved in the regulation of lipid
metabolism and synaptic vesicle trafficking. A growing body of evidence suggests that
alterations in lipid profile, which were observed in both brain and plasma, can be directly
linked to the onset of α-Syn aggregation. We hypothesize that the toxicity of α-Syn
aggregates is determined by their structure, which in turn is controlled by the lipid
composition of neuronal membranes. Our group pioneered development of a label-free,
non-invasive and non-destructive approach that can be used to determine the structural
organization of individual α-Syn aggregates. We will use this innovative biophysical
imaging approach to unravel protein secondary structure of α-Syn oligomers grown in the
presence of different lipids. We will investigate toxicity of these oligomers on primary
dopaminergic neurons from midbrain, striatal, and cortical areas of the mouse brains. This
will reveal the relationship between the structure of α-Syn oligomers and their toxicity. The
proposed work also aims to determine the extent to which α-Syn oligomers with different
structures exert toxic effects to the specific subsets of neurons.
摘要
帕金森病(PD)是第二常见的神经退行性疾病,
影响着全世界近500万人。帕金森病与细胞内
α-突触核蛋白的聚集(α-Syn),这是一种参与脂质调节的小蛋白
新陈代谢和突触小泡运输。越来越多的证据表明
在大脑和血浆中都观察到的血脂谱的变化可以直接
与α-SYN聚集的开始有关。我们假设α-syn的毒性
聚集体由其结构决定,而其结构又受脂质控制
神经细胞膜的组成。我们团队率先开发了一种无标签、
非侵入性和非破坏性的方法,可用于确定结构
单个α-SYN聚合的组织。我们将利用这种创新的生物物理
α-SYN低聚物蛋白质二级结构的成像研究
存在不同的脂类。我们将研究这些低聚物对初级细胞的毒性。
小鼠大脑中脑、纹状体和皮质区的多巴胺能神经元。这
将揭示α-Syn低聚体的结构与其毒性之间的关系。这个
拟议的工作还旨在确定α-Syn寡聚体在多大程度上与不同的
结构对特定的神经元亚群产生毒性作用。
项目成果
期刊论文数量(33)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Solid-to-Liposome Conformational Transition of Phosphatidylcholine and Phosphatidylserine Probed by Atomic Force Microscopy, Infrared Spectroscopy, and Density Functional Theory Calculations.
- DOI:10.1021/acs.analchem.2c03061
- 发表时间:2022-09-27
- 期刊:
- 影响因子:7.4
- 作者:Dou, Tianyi;Zens, Clara;Schroeder, Katrin;Jiang, Yuan;Makarov, Alexey A.;Kupfer, Stephan;Kurouski, Dmitry
- 通讯作者:Kurouski, Dmitry
The toxicities of A30P and A53T α-synuclein fibrils can be uniquely altered by the length and saturation of fatty acids in phosphatidylserine.
- DOI:10.1016/j.jbc.2023.105383
- 发表时间:2023-12
- 期刊:
- 影响因子:4.8
- 作者:Ali, Abid;Zhaliazka, Kiryl;Dou, Tianyi;Holman, Aidan P.;Kurouski, Dmitry
- 通讯作者:Kurouski, Dmitry
Advances of Vibrational Circular Dichroism (VCD) in bioanalytical chemistry. A review.
- DOI:10.1016/j.aca.2017.08.014
- 发表时间:2017-10-16
- 期刊:
- 影响因子:6.2
- 作者:Kurouski, Dmitry
- 通讯作者:Kurouski, Dmitry
Nanoscale imaging of individual amyloid aggregates extracted from brains of Alzheimer and Parkinson patients reveals presence of lipids in α-synuclein but not in amyloid β1-42 fibrils.
从阿尔茨海默病和帕金森病患者大脑中提取的单个淀粉样蛋白聚集体的纳米级成像揭示了α-突触核蛋白中存在脂质,但淀粉样蛋白β1-42 原纤维中不存在脂质。
- DOI:10.1002/pro.4598
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Zhaliazka,Kiryl;Kurouski,Dmitry
- 通讯作者:Kurouski,Dmitry
Elucidation of Secondary Structure and Toxicity of α-Synuclein Oligomers and Fibrils Grown in the Presence of Phosphatidylcholine and Phosphatidylserine.
阐明在磷脂酰胆碱和磷脂酰丝氨酸存在下生长的α-突触核蛋白寡聚物和原纤维的二级结构和毒性。
- DOI:10.1021/acschemneuro.3c00314
- 发表时间:2023
- 期刊:
- 影响因子:5
- 作者:Dou,Tianyi;Matveyenka,Mikhail;Kurouski,Dmitry
- 通讯作者:Kurouski,Dmitry
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Dmitry Kurouski其他文献
Dmitry Kurouski的其他文献
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{{ truncateString('Dmitry Kurouski', 18)}}的其他基金
Biophysical determination of the underlying cause of α-Syn oligomer toxicity
α-Syn 寡聚物毒性根本原因的生物物理测定
- 批准号:
10671496 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
Biophysical determination of the underlying cause of α-Syn oligomer toxicity
α-Syn 寡聚物毒性根本原因的生物物理测定
- 批准号:
10461936 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
Biophysical determination of the underlying cause of α-Syn oligomer toxicity
α-Syn 寡聚物毒性根本原因的生物物理测定
- 批准号:
10275841 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
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