Behind the curtain of tauopathy: a show of multiple players orchestrating tau toxicity

Abstract

tau, a microtubule-associated protein, directly binds with microtubules to dynamically regulate the organization of cellular cytoskeletons, and is especially abundant in neurons of the central nervous system. Under disease conditions such as Pick's disease, progressive supranuclear palsy, frontotemporal dementia, parkinsonism linked to chromosome 17 and Alzheimer's disease, tau proteins can self-assemble to paired helical filaments progressing to neurofibrillary tangles. In these diseases, collectively referred to as "tauopathies", alterations of diverse tau modifications including phosphorylation, metal ion binding, glycosylation, as well as structural changes of tau proteins have all been observed, indicating the complexity and variability of factors in the regulation of tau toxicity. Here, we review our current knowledge and hypotheses from relevant studies on tau toxicity, emphasizing the roles of phosphorylations, metal ions, folding and clearance control underlining tau etiology and their regulations. A summary of clinical efforts and associated findings of drug candidates under development is also presented. It is hoped that a more comprehensive understanding of tau regulation will provide us with a better blueprint of tau networking in neuronal cells and offer hints for the design of more efficient strategies to tackle tau-related diseases in the future.

Keywords: Chaperon; Degradation; Hyperphosphorylation; Therapeutic strategy; Zinc.

Fig. 1

The multiple layers of modifications on tau proteins. The major domain composition of tau protein (the longest isoform, 441 amino acid), including the N-terminus, proline-rich region, microtubule-binding repeat (microtubule-binding domain), and the C-terminus, is illustrated here. Modifying events such as phosphorylation, acetylation, metal binding, truncations and disease-related mutations are listed above or below the schematic tau protein. These represent only a partial list of tau modifications. Some other modifications such as glycosylation, glycation, prolyl-isomerization, nitration and sumoylation, which could also affect the function and toxicity of tau, are not shown. Specifically, acting sites of kinases (MARK, GSK3 and CDK5) and the metal binding sites of tau are marked; several tau mutations such as K257T, G272V, ∆K280, P301L/S, K369I, V337M, G389R and R406W have been widely used in model organism studies and are listed; some known acetylation sites as well as the cleavage on D421 and E391 are also drawn in this schematic presentation (it is found that caspase-3 mediates D421 cleavage, but the mechanism of E391 cleavage remains unclear)

Fig. 2

A model showing some of the mechanisms regulating tau toxicity. The physiological binding of tau to MTs (microtubules) is regulated by kinases (GSK3, CDK5 and MARK) and phosphatases (like PP2A). Under pathological conditions, tau is misregulated (such as abnormal phosphorylation and mutation) and dissociates from MTs, “freeing” tau and destabilizing the MTs (leading to MT depolymerization and cargo transporting defects). Abnormal modifications (hyperphosphorylation, metal ion, acetylation, glycosylation, glycation, prolyl-isomerization, cleavage or truncation, nitration and sumoylation) also result in tau aggregation, oligomer formation progressing to more advanced aggregates (like NFTs or neurofibrillary tangles). Metal ions, though also possibly affecting hyperphosphorylation, largely act to bind tau and work in parallel with phosphorylation to facilitate tau aggregation. The abnormally modified tau and tau aggregates can interfere with neuronal functions and lead to neuronal toxicity. To combat tau toxicity, molecular chaperons like Hsp70/Hsc70 can refold the abnormal tau, the proteasome system can degrade the abnormal tau species, and the autophagy apparatus can eliminate tau oligomers and higher order or insoluble aggregates. Dysfunction of these refolding and clearance systems can exacerbate tau pathology