The acetylation of tau inhibits its function and promotes pathological tau aggregation
By T. Cohen, Jing L Guo, David E Hurtado, L. Kwong, Ian P. Mills, John Q. Trojanowski, V. Lee. Nature Communications, 2011
684 citations recorded by the source corpus.
The microtubule associated protein tau promotes neuronal survival through binding and stabilization of MTs. Phosphorylation regulates tau–microtubule interactions and hyperphosphorylation contributes to the aberrant formation of insoluble tau aggregates in Alzheimer’s disease (AD) and related tauopathies1. However, other pathogenic post-translational tau modifications have not been well characterized. Here we demonstrate that tau acetylation inhibits tau function via impaired tau–microtubule interactions and promotes pathological tau aggregation. Mass spectrometry analysis identified specific lysine residues, including lysine 280 (K280) within the microtubule-binding motif as the major sites of tau acetylation. Immunohistochemical and biochemical studies of brains from tau transgenic mice and patients with AD and related tauopathies showed that acetylated tau pathology is specifically associated with insoluble, Thioflavin-positive tau aggregates. Thus, tau K280 acetylation in our studies was only detected in diseased tissue, suggesting it may have a role in pathological tau transformation. This study suggests that tau K280 acetylation is a potential target for drug discovery and biomarker development for AD and related tauopathies.
Subfields: Molecular Biology, Pharmacology, Physiology
View Paper: https://www.semanticscholar.org/paper/ad7906b4812cbc626c1d90a2ca2eb64335d7be08
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Molecular Biology
- John Q. Trojanowski
- Guy C. Brown
- Michael Coleman
- V. Lee
- V. Borutaite
- E. Mandelkow
- L. Mucke
- M. Fricker
In Pharmacology
In Physiology
- V. Lee
- E. Mandelkow
- Jing L Guo
- John Q. Trojanowski
- Bin Zhang
- Guy C. Brown
- A. Tolkovsky
- Michael Coleman
Citations in the corpus
- Biochemistry and cell biology of tau protein in neurofibrillary degeneration. (2012, background): “Acetylation of lysines affects predominantly K280, impairs MT binding of Tau, promotes aggregation and potentially interferes with ubiquitination and thus degradation of Tau (Cohen et al. 2011; Min et al. 2010).”
- Synthetic Tau Fibrils Mediate Transmission of Neurofibrillary Tangles in a Transgenic Mouse Model of Alzheimer’s-like Tauopathy (2013, background): “(3) Using a polyclonal antibody specific for ac-K280 tau, we found that pff-induced tau tangles were acetylated similar to human AD and other tauopathy brains (Cohen et al., 2011; Irwin et al., 2012), whereas acetylated tau is hardly detected in uninjected aged symptomatic PS19 mice.”
- Neuronal Cell Death. (2018, positive): “In addition to phosphorylation, tau can also be modified by other posttranslational mechanisms, including lysine methylation and ubiquitylation (673) and acetylation (126), with acetylation being proposed to be a leading cause of degeneration in a mouse model of tau-mediated neurodegeneration (468).”
- Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “Lys280 acetylation enhances fibrillization, whereas Lys274 and Lys281 acetylation promotes tau distribution to the soma and dendrites, and resulting in synaptic and cognitive dysfunction [157, 158, 160].”
- The world of protein acetylation. (2016, background): “Acetylation of tau K280 was found in several human tauopathies [445].”
- The Many Faces of Tau (2011, background): “, 2010), alter its microtubule binding and enhance aggregation (Cohen et al., 2011).”