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

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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.

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Abbreviations

Aβ:

β-Amyloid

AD:

Alzheimer’s disease

BBB:

Blood–brain barrier

CHIP:

Carboxyl terminus of Hsc70 interacting protein

CMA:

Chaperone-mediated autophagy

CNS:

Central nervous system

CQ:

Clioquinol

FKBP51 and FKBP52:

FK506-binding protein 51 and 52

FTDP-17:

Frontotemporal dementia and parkinsonism linked to chromosome 17

LTP:

Long-term potentiation

MAP:

Microtubule-associated protein

MAPT:

Microtubule-associated protein tau

MARK:

Microtubule/MAP-affinity regulating kinase

MT:

Microtubule

NFTs:

Neurofibrillary tangles

NMNAT2:

Nicotinamide mononucleotide adenylyltransferase 2

PHFs:

Paired helical filaments

PP2A:

Protein phosphatase-2A

PSP:

Progressive supranuclear palsy

PTP1B:

Protein tyrosine phosphatase 1B

TMAO:

Trimethylamine N-oxide

3-MA:

3-Methylamphetamine

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Acknowledgments

We apologize for our likely omissions as well as inability to cite all relevant and important works in this review due to size limitation. We thank Tory Johnson (Stanford University, USA) and Richard Jiang Yang (Dartmouth College, New Hampshire, United States) for English editing. Our own research was primarily supported by the National Basic Research Program of China (2013CB910700) and by the National Science Foundation of China (31123004).

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  1. State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China

    Yunpeng Huang & Bing Zhou

  2. Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Zhihao Wu

  3. Beijing Institute for Brain Disorders, Beijing, China

    Bing Zhou

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  1. Yunpeng Huang
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Correspondence to Bing Zhou.

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Huang, Y., Wu, Z. & Zhou, B. Behind the curtain of tauopathy: a show of multiple players orchestrating tau toxicity. Cell. Mol. Life Sci. 73, 1–21 (2016). https://doi.org/10.1007/s00018-015-2042-8

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