Acetylation mimic of lysine 280 exacerbates human Tau neurotoxicity in vivo

Abstract

Dysfunction and accumulation of the microtubule-associated human Tau (hTau) protein into intraneuronal aggregates is observed in many neurodegenerative disorders including Alzheimer’s disease (AD). Reversible lysine acetylation has recently emerged as a post-translational modification that may play an important role in the modulation of hTau pathology. Acetylated hTau species have been observed within hTau aggregates in human AD brains and multi-acetylation of hTau in vitro regulates its propensity to aggregate. However, whether lysine acetylation at position 280 (K280) modulates hTau-induced toxicity in vivo is unknown. We generated new Drosophila transgenic models of hTau pathology to evaluate the contribution of K280 acetylation to hTau toxicity, by analysing the respective toxicity of pseudo-acetylated (K280Q) and pseudo-de-acetylated (K280R) mutant forms of hTau. We observed that mis-expression of pseudo-acetylated K280Q-hTau in the adult fly nervous system potently exacerbated fly locomotion defects and photoreceptor neurodegeneration. In addition, modulation of K280 influenced total hTau levels and phosphorylation without changing hTau solubility. Altogether, our results indicate that pseudo-acetylation of the single K280 residue is sufficient to exacerbate hTau neurotoxicity in vivo, suggesting that acetylated K280-hTau species contribute to the pathological events leading to neurodegeneration in AD.

Tau Structures

“…Lysine 280 loss facilitates tau self-assembly and exacerbates tau toxicity (Gorsky et al, 2016; Wang and Mandelkow, 2016). …”

The Role of the Carboxyl-Terminal Sequence of Tau and MAP2 in the Pathogenesis of Dementia

“…Most MAPT mutations, such as G272V, V337M and R406W and post-translational modifications including acetylation, O-GlcNAc modification and phosphorylation, are located on the carboxyl terminal of tau (Goedert et al, 1998; Spillantini and Goedert, 2000; Mandelkow and Mandelkow, 2012; Yuzwa et al, 2012). Acetylation of K280, which is localized in MTBD, accelerates pathological tau aggregation and increases tau neurotoxicity in vivo (Cohen et al, 2011; Gorsky et al, 2016). Deletion of K280 strikingly enhances the aggregation propensity and cellular toxicity of tau, despite a decrease in the expression of 4R-tau (Khlistunova et al, 2006; Mocanu et al, 2008; Momeni et al, 2009).…”

Developmental Expression of 4-Repeat-Tau Induces Neuronal Aneuploidy in Drosophila Tauopathy Models

“…Interestingly, using the same system, a recent study has shown cellular ablation of adult neuronal structures called mushroom bodies arising during embryonic development suggesting an important role for 4R-Tau during neurodevelopment21. In addition, using a gene switch system to control Tau expression, it was shown that 4R-Tau adult-onset expression does not affect adult life span2223. Thus, while a strong focus has been put on deciphering 4R-Tau toxicity in post-mitotic neuronal cells, it remains unclear whether adult 4R-Tau toxicity requires a neurodevelopmental component.…”