Role of Transglutaminase 2 in Synucleinopathies

转谷氨酰胺酶 2 在突触核蛋白病中的作用

• 批准号: 10285001
• 负责人: M. Maral Mouradian
• 金额: $ 43.18万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285001
• 关键词: Address; Affect; Amyloid Fibrils; Anatomy; Animal Model; Animals; Attenuated; Behavioral; Biological Models; Brain; Brain Diseases; Brain region; Cells; Cerebrospinal Fluid; Data; Dementia with Lewy Bodies; Disease; Disease Progression; Endopeptidase K; Exhibits; Genes; Genetic; Glutamine; Goals; Guanosine Triphosphate Phosphohydrolases; Human; In Vitro; Injections; Investigation; Knock-out; Knowledge; Lewy Bodies; Lewy neurites; Lysine; Mammalian Cell; Mediating; Modeling; Molecular; Molecular Conformation; Molecular Weight; Motor; Mus; Nature; Nerve Degeneration; Neurons; Outcome; Parkinson Disease; Parkinson' s Dementia; Pathogenicity; Pathologic; Pathologic Processes; Pathology; Patients; Performance; Phenotype; Play; Process; Protein Disulfide Isomerase; Protein-Serine-Threonine Kinases; Proteins; Proteolysis; Resistance; Role; Seeds; Severities; Stress; Study models; Substantia nigra structure; Testing; Therapeutic; Thioflavin S; Transgenic Mice; Transgenic Organisms; Transglutaminases; Wild Type Mouse; Yeasts; alpha synuclein; base; behavioral phenotyping; crosslink; design; dopaminergic neuron; inhibitor/antagonist; mRNA Expression; monomer; mutant; neuroinflammation; phenotypic biomarker; preservation; protein aggregation; protein expression; response; synucleinopathy; transglutaminase 2

Project Summary: α-Synuclein is a key pathogenic protein in Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) based on genetic, neuropathologic, cell biologic and animal model studies. This intrinsically disordered protein can oligomerize, misfold, and form fibrils that propagate across neurons in the brain and accumulate in Lewy bodies and Lewy neurites. It is believed that the oligomeric forms of α-synuclein represent the toxic species, and these can nucleate monomers to perpetuate the pathologic process underlying the progressive nature of the disease. Thus, understanding the factors that trigger the initial steps of oligomerization is critical for designing disease modifying therapeutic strategies. A hitherto under-explored factor is molecular cross- linking of α-synuclein by transglutaminase 2 (TG2) between glutamine and lysine residues creating intermolecular isopeptide bonds that are highly resistant to proteolysis. Several lines of evidence indicate that TG2 cross-links α-synuclein leading to its aggregation in vitro, in cultured mammalian cells, in yeast cells, and in the brains of transgenic mice. We have found that the phenotype of α-synuclein transgenic mice is exacerbated by over-expressing TG2 and is mitigated by knocking it out. Studies in patients with α-synucleinopathy also corroborate the hypothesis that TG2 plays a pathogenetic role. TG2 expression is increased in the substantia nigra and cerebrospinal fluid of PD patients compared with control subjects, TG2 co-localizes with α-synuclein aggregates in stressed dopaminergic neurons in PD brains, and TG2-catalyzed cross-links co-localize with α-synuclein in Lewy bodies in PD and DLB affected brains. Despite this body of evidence, it remains unknown whether TG2-mediated cross-linking of α-synuclein promotes the propagation of these aggregates across the brain. We hypothesize that it does and propose to test this hypothesis through two specific aims: 1) Investigate if the presence of TG2 and its expression level influence the propagation of α-synuclein fibrils, and 2) Examine if the transglutaminase enzymatic activity of TG2 is responsible for this process. Knowledge gained from these studies will address a fundamental scientific question about the pathogenetic mechanism of TG2-mediated α-synuclein propagation and aid in developing targeted disease modifying therapeutic for synucleinopathies.

项目摘要： α-突触核蛋白是帕金森氏病（PD）和痴呆的关键致病蛋白 基于遗传，神经病理，细胞生物学和动物模型研究的身体（DLB）。这 本质上受到干扰的蛋白质会呈寡聚，错误折叠和形成纤维，并在 大脑中的神经元，积聚在路易的身体和路易神经元中。相信 α-突触核蛋白的寡聚形式代表有毒物种，这些可以核单体 为了使疾病进步性质的基础病理过程永存。那， 了解触发低聚的初始步骤的因素对于设计至关重要 疾病修改治疗策略。迄今为止探索的因子是分子交叉 通过谷氨酰胺2（TG2）在谷氨酰胺和赖氨酸残基之间通过α-核蛋白连接 产生对蛋白水解具有高度抗性的分子间无菌键。几行 证据表明TG2交叉链接α-突触核蛋白导致其体外聚集，在培养中 哺乳动物细胞，酵母细胞和转基因小鼠的大脑。我们发现 α-突触核蛋白转基因小鼠的表型通过过度表达的TG2加剧，IS 通过将其淘汰来缓解。 α-突触核疾病患者的研究也证实了 TG2起致病作用的假设。 TG2表达在质量中增加 与对照组相比，PD患者的NIGRA和脑脊液液，TG2与 PD大脑中应力多巴胺能神经元中的α-核蛋白聚集体，并催化TG2催化 交叉链接与PD和DLB影响大脑的Lewy体中的α-突触核蛋白共定位。尽管 这一证据，尚不清楚TG2介导的α-突触核蛋白的交联 促进这些聚集体在整个大脑中的传播。我们假设它确实如此， 提议通过两个具体目的检验该假设：1）研究是否存在TG2 及其表达水平影响α-核蛋白原纤维的传播，以及2）检查是否是否 TG2的转谷氨酰胺酶酶活性是为此造成的。知识获得了 从这些研究中将解决有关致病性的基本科学问题 TG2介导的α-突触核蛋白传播的机制，有助于发展靶向疾病 修饰触突变的治疗。