Human tau compromises neuronal structural integrity in C. elegans promoted by age, stress and phosphorylation
Joshi, M.; van Falier, S. J. A.; Sinnige, T.
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Tauopathies are a group of progressive neurodegenerative diseases amongst which Alzheimers disease is the most prevalent. They typically have a late age of onset and lead to cognitive decline. Tau is a highly soluble, intrinsically disordered microtubule binding protein that aggregates in these diseases. The mechanisms by which age-associated changes alter tau functionality and compromise neuronal structural integrity remain poorly understood. Here, we show with the use of single-copy gene insertion Caenorhabditis elegans models that human tau preferentially localises to neuronal processes in the nematode, consistent with its function of binding to microtubules. The expression of tau in the nervous system leads to age-associated changes in neuronal structural integrity. The observed "buckling" phenotype was exacerbated by exposure of the animals to different stressors which are known to enhance tau phosphorylation. Expressing phosphomimic tau or co-expressing human kinases both severely worsened the buckling phenotype. Kinase expression additionally induced tau inclusions in a small proportion of animals. These results point to an interplay between ageing, stress and phosphorylation leading to structural changes in neuronal processes prior to widespread tau aggregation.
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