Modifications of the tau protein and their varied effects on aggregation and function

Abstract

Tau is a microtubule-associated protein that is typically found in the axons of neurons. Six isoforms of the protein can be generated through alternative mRNA splicing and all are found in the adult brain. The protein is closely associated with a group of neurodegenerative diseases, including Alzheimer's disease, collectively known as tauopathies. In these diseases tau dissociates from microtubules and begins to polymerize into aggregates that are typically fibrillary in nature. The deposition of these aggregates is closely linked to the death and dysfunction of neurons and eventually leads to atrophy of specific regions of the brain. Tauopathies display a wide variety of pathologies that distinguish them from each other, including aggregate morphology and isoform inclusion. Differential conformational changes in pathological forms of the protein may affect its propensity for aggregation and function. Hyperphosphorylation of tau or inherited mutations, known as FTDP-17 mutations, may induce these conformational changes and alter aggregation and function. The studies described here used in vitro assays to determine how hyperphosphorylation affects each of the tau isoforms and how various FTDP-17 mutations can alter aggregation and function. This information helps to describe how intrinsic differences due to modifications of tau can manifest themselves in the varying pathologies of tauopathies. This can be applied to C. elegans models of tauopathies to determine the effects in living neurons. The results demonstrate that similar phosphorylation patterns in tau can result in very different effects on the protein's aggregation and ability to stabilize microtubule polymerization depending on the isoform background. This suggests that phosphorylation pattern is sufficient to induce differential aggregation and may affect the morphology and isoform contents of aggregates. Similarly, FTDP-17 mutations also induced very different effects on tau aggregation and function. This indicates that these mutations may be affecting disease pathologies in very different manners. Differences between tau isoforms and FTDP-17 mutations are likely affecting the phenotypes seen in animal models of disease and should not be ignored. This is being tested by developing several unique C. elegans models of tauopathies.