Assembly of recombinant tau into filaments identical to those of
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Descrição
Many neurodegenerative diseases, including Alzheimer’s disease, the most common form of dementia, are characterised by knotted clumps of a protein called tau. In these diseases, tau misfolds, stacks together and forms abnormal filaments, which have a structured core and fuzzy coat. These sticky, misfolded proteins are thought to be toxic to brain cells, the loss of which ultimately causes problems with how people move, think, feel or behave. Reconstructing the shape of tau filaments using an atomic-level imaging technique called electron cryo-microscopy, or cryo-EM, researchers have found distinct types of tau filaments present in certain diseases. In Alzheimer’s disease, for example, a mixture of paired helical and straight filaments is found. Different tau filaments are seen again in chronic traumatic encephalopathy (CTE), a condition associated with repetitive brain trauma. It remains unclear, however, how tau folds into these distinct shapes and under what conditions it forms certain types of filaments. The role that distinct tau folds play in different diseases is also poorly understood. This is largely because researchers making tau proteins in the lab have yet to replicate the exact structure of tau filaments found in diseased brain tissue. Lövestam et al. describe the conditions for making tau filaments in the lab identical to those isolated from the brains of people who died from Alzheimer’s disease and CTE. Lövestam et al. instructed bacteria to make tau protein, optimised filament assembly conditions, including shaking time and speed, and found that bona fide filaments formed from shortened versions of tau. On cryo-EM imaging, the lab-produced filaments had the same left-handed twist and helical symmetry as filaments characteristic of Alzheimer’s disease. Adding salts, however, changed the shape of tau filaments. In the presence of sodium chloride, otherwise known as kitchen salt, tau formed filaments with a filled cavity at the core, identical to tau filaments observed in CTE. Again, this structure was confirmed on cryo-EM imaging. Being able to make tau filaments identical to those found in human tauopathies will allow scientists to study how these filaments form and elucidate what role they play in disease. Ultimately, a better understanding of tau filament formation could lead to improved diagnostics and treatments for neurodegenerative diseases involving tau.
Laboratory-based methods are presented that produce filamentous tau aggregates with the same structures as those observed in neurodegenerative disease.
Laboratory-based methods are presented that produce filamentous tau aggregates with the same structures as those observed in neurodegenerative disease.
Chemical Synthesis of Microtubule-Associated Protein Tau
RCSB PDB - 7QK2: In vitro assembled 300-391 tau filaments in PBS (36a)
Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau, Acta Neuropathologica Communications
Cryo-EM structure of RNA-induced tau fibrils reveals a small C-terminal core that may nucleate fibril formation
Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau, Acta Neuropathologica Communications
RCSB PDB - 7QJV: In vitro assembled tau filaments into Quadruple Helical Filaments type 1 (2c)
Assembly of recombinant tau into filaments identical to those of Alzheimer's disease and chronic traumatic encephalopathy
Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold
Assembly of recombinant tau into filaments identical to those of Alzheimer's disease and chronic traumatic encephalopathy
Assembly of recombinant tau into filaments identical to those of Alzheimer's disease and chronic traumatic encephalopathy
RCSB PDB - 7QK5: In vitro assembled 266/297 - 391 tau filaments with KCl (10a)
Assembly of recombinant tau into filaments identical to those of Alzheimer's disease and chronic traumatic encephalopathy
Assembly of recombinant tau into filaments identical to those of Alzheimer's disease and chronic traumatic encephalopathy
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