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- W2103019497 abstract "A major hallmark of Alzheimer's disease is aggregation of tau, a microtubule-associated protein, into paired-helical filaments and deposition into neurofibrillary tangles. Tau aggregation is also seen in other neurodegenerative diseases, collectively known as tauopathies. The morphology, content and location of the aggregates, as well as the location of the neurodegeneration, can vary by disorder. Tauopathies are typically sporadic, but, several mutations in tau have been identified as being associated with a heritable dominant-negative phenotype seen in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). While this indicates a clear link between tau dysfunction and neurodegeneration, there are many questions surrounding the causes of aggregation and how tau is inducing toxicity, as evidenced by different FTDP-17 mutations giving rise to different phenotypes. The various FTDP-17 mutations could differentially affect the secondary structure of the protein, its phosphorylation state, or the presence of nucleating sequences associated with aggregation induction. All of these changes could then affect the aggregation propensity of the protein. Determining how tau is affected by these mutations and how these changes affect aggregation could be an important first step in preventing toxic aggregation. In this study, site-directed mutagenesis was used to create several FTDP-17 mutants, in a full-length tau backbone. The mutants were chosen based on predictions for which would cause the largest effects on the hydrophobicity, charge, and local secondary structure of the protein. Tau aggregation was modeled using in vitro reactions, with arachidonic acid as a polymerization inducer molecule. The total amount of aggregation, the types of aggregates, and the ability of the protein to stabilize microtubule assembly varied among the different mutants with some correlation to the type of effect the mutation had on various properties of the protein. These results indicate that changes to secondary structural elements, protein charge, local hydrophobicity, and the formation of nucleating sequences caused by FTDP-17 mutations have differential effects on the function and dysfunction of tau." @default.
- W2103019497 created "2016-06-24" @default.
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- W2103019497 date "2012-07-01" @default.
- W2103019497 modified "2023-09-27" @default.
- W2103019497 title "P3-003: Structural and functional modification of tau by FTDP-17 mutations" @default.
- W2103019497 doi "https://doi.org/10.1016/j.jalz.2012.05.1221" @default.
- W2103019497 hasPublicationYear "2012" @default.
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