Abstract
INTRODUCTION
Aggregation of hyperphosphorylated tau (tauopathy) is associated with cognitive impairment in patients with Alzheimer’s disease (AD). In AD, a metabolic shift due to the Warburg effect results in increased lactate production. Lactate can induce a post-translational modification (PTM) on proteins that conjugates lactyl groups to lysine (K) residues, which is known as lactylation.
METHODS
We analyzed lactylation of tau in control and AD brain tissue and conducted cell-based assays. In addition, we used in vitro assays to determine whether p300 catalyzed tau lactylation.
RESULTS
Quantitative proteomics detected that tau lactylation was elevated in AD brains, with K residue at position 331 (K331) being a prominent site. Lactate induced tau lactylation, which increased tau phosphorylation and cleavage and reduced ubiquitination. Inhibition of lactate production lowered tau lactylation; p300 catalyzed tau lactylation.
DISCUSSION
Our findings suggest that tau lactylation links metabolic dysregulation with tauopathy and could serve as a novel diagnostic and therapeutic target.
Highlights
Elevated tau lactylation, particularly at K331, is evident in in human AD brain samples.
Lactate induces tau lactylation, enhancing phosphorylation and cleavage while inhibiting ubiquitination.
The acetyl-transferase p300 catalyzes tau lactylation, with K331 being the most prominent site.
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This post is Copyright: Xiaoyu Zhang,
Yan Liu,
Michaella J. Rekowski,
Ning Wang | December 31, 2024