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Role of Transglutaminase 2 in Synucleinopathies

转谷氨酰胺酶 2 在突触核蛋白病中的作用

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目总结: