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The self-assembly of Tau protein into amyloid structures is associated with Alzheimer's disease and other tauopathies. Dominant familial mutations in the Tau gene, such as P301L and P301S, increase the propensity of the Tau protein to aggregate abnormally into filaments. A quantitative description of the fibrillization process of Tau will facilitate the understanding of the cytotoxicity of Tau aggregates and their intercellular spreading. Here, we investigated the aggregation kinetics of Tau and disease-associated P301L and P301S mutants by combined thioflavin T assay and kinetic modeling, which revealed the rate constants of individual microscopic steps in the process of amyloid formation. Compared to WT Tau, P301L shows a larger primary nucleation rate while P301S has higher elongation and fragmentation rates and a more apparent fibril annealing process. Cross-seeding assays and FRET experiments indicate that the structures of the fibrillar nuclei of the three variants are distinct. These results provide detailed insights into how the amyloid aggregation mechanism of Tau protein is affected by the familial mutations P301L and P301S, and relates the physical properties of Tau mutants to their pathogenic mechanism.
This article was published in the following journal.
Name: Physical chemistry chemical physics : PCCP
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Techniques for separating distinct populations of cells.
The formation of clumps of RED BLOOD CELLS under low or non-flow conditions, resulting from the attraction forces between the red blood cells. The cells adhere to each other in rouleaux aggregates. Slight mechanical force, such as occurs in the circulation, is enough to disperse these aggregates. Stronger or weaker than normal aggregation may result from a variety of effects in the ERYTHROCYTE MEMBRANE or in BLOOD PLASMA. The degree of aggregation is affected by ERYTHROCYTE DEFORMABILITY, erythrocyte membrane sialylation, masking of negative surface charge by plasma proteins, etc. BLOOD VISCOSITY and the ERYTHROCYTE SEDIMENTATION RATE are affected by the amount of erythrocyte aggregation and are parameters used to measure the aggregation.
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Neurology - Central Nervous System (CNS)
Alzheimer's Disease Anesthesia Anxiety Disorders Autism Bipolar Disorders Dementia Epilepsy Multiple Sclerosis (MS) Neurology Pain Parkinson's Disease Sleep Disorders Neurology is the branch of me...