Structure and Mechanism of Action of Tau Aggregation Inhibitors

Cisek, Katryna; Cooper, Grace L.; Huseby, Carol J.; Kuret, Jeffrey Allan

doi:10.2174/1567205011666141107150331

Cited by 83 publications

(64 citation statements)

References 126 publications

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“…The crystal structure of the PHF6 peptide, describing the steric zipper with a dry interface (42), has spurred a large research effort both to interpret at the structural level aggregation inhibitors described in the past (62)(63)(64) or to rationally develop novel inhibitors (62,65,66). Many of these were tested first in an in vitro assay monitoring the polyanion-induced aggregation of some Tau construct before being tested in a cell model or a transgenic organism.…”

Section: Jbc Reviews: Cryo-em Of Taumentioning

confidence: 99%

Elucidating Tau function and dysfunction in the era of cryo-EM

Lippens

Gigant

2019

Journal of Biological Chemistry

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Edited by Paul E. FraserTau is a microtubule-associated protein involved in the regulation of axonal microtubules in neurons. In pathological conditions, it forms fibrils that are molecular hallmarks of neurological disorders known as tauopathies. In the last 2 years, cryo-EM has given unprecedented high-resolution views of Tau in both physiological and pathological conditions. We review here these new findings and put them into the context of the knowledge about Tau before this structural breakthrough. The first structures of Tau fibrils, a molecular hallmark of Alzheimer's disease (AD), were based on fibrils from the brain of an individual with AD and, along with similar patient-derived structures, have set the gold standard for the field. Cryo-EM structures of Tau fibers in three distinct diseases, AD, Pick's disease, and chronic traumatic encephalopathy, represent the end points of Tau's molecular trajectory. We propose that the recent Tau structures may call for a re-examination of databases that link different Tau variants to various forms of dementia. We also address the question of how this structural information may link Tau's functional and pathological aspects. Because this structural information on Tau was obtained in a very short period, the new structures should be viewed in light of earlier structural observations and past and present functional data to shed additional light on Tau function and dysfunction.

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Section: Jbc Reviews: Cryo-em Of Taumentioning

confidence: 99%

Elucidating Tau function and dysfunction in the era of cryo-EM

Lippens

Gigant

2019

Journal of Biological Chemistry

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“…Considering their effect on tau monomers, these agents are believed to act at early stage in the tauopathies. A number of tau aggregation inhibitors have been tested in vitro, however in vivo studies are limited due to their toxicity [107].…”

Section: Tau Aggregation Inhibitorsmentioning

confidence: 99%

Preclinical, phase I, and phase II investigational clinical trials for treatment of progressive supranuclear palsy

Shoeibi

Olfati

Litvan

2018

Expert Opinion on Investigational Drugs

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Our understanding of the pathological basis of progressive supranuclear palsy (PSP), as the most common atypical parkinsonian syndrome, has greatly increased in recent years and a number of disease-modifying therapies are under evaluation as a result of these advances. Areas covered: In this review, we discuss disease-modifying therapeutic options which are currently under evaluation or have been evaluated in preclinical or clinical trials based on their targeted pathophysiologic process. The pathophysiologic mechanisms are broadly divided into three main categories: genetic mechanisms, abnormal post-translational modifications of tau protein, and transcellular tau spread. Expert opinion: Once the best therapeutic approaches are identified, it is likely that some combination of interventions will need to be evaluated, but this will take time. It is critical to treat patients at early stages, and development of the Movement Disorder Society PSP diagnostic criteria is an important step in this direction. In addition, development of biological biomarkers such as tau PET and further refinement of tau ligands may help both diagnose early and measure disease progression. In the meantime, a comprehensive, personalized interdisciplinary approach to this disease is absolutely necessary.

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“…Furthermore, small molecules belonging to TAIs have already been developed and tested in humans [29,34,35], even if with discrepancy between the cell-based and/or in vitro data and the in vivo efficacy. Important pharmaceutical implications have been rising from the possibility to distinguish the tau-tau binding interaction from the tautubulin binding one with new aggregation inhibitors [36,37].…”

Section: Tau Aggregation Inhibitormentioning

confidence: 99%