Alzheimer's disease (AD), one of the major pathological changes is the neurofibrillary tangles that result from the over-phosphorylation of microtubule-binding protein Tau in the brain cells of patients. In addition to AD, there are also hyper-phosphorylation of Tau and formation of neurofibrillary tangles during the pathogenesis of several other neurodegenerative diseases, collectively referred to as tauopathies. Under normal physiological conditions, Tau protein acts as a stabilizing microtubule, but Tau protein is dysfunctional in the brains of patients with Tauopathies, resulting in destruction of the microtubule structure. Previous studies by Zhang Yongqing, a research team at the Institute of Genetics and Development, showed that in a transgenic Drosophila model of Tauopathy, heterologously expressed Tau is hyper-phosphorylated and results in decreased density of microtubules and destruction of the network. Histone deacetylase family members HDAC6 mutation can be effectively inhibited Tau heterologous expression of microtubule damages, and HDAC6 specific point mutation function analysis and specific inhibition of HDAC6 microtubule deacetylase activity of drug treatment experiments. The results show that HDAC6 mutation and activity destruction probably rescues Tau-induced microtubule destruction by increasing microtubule acetylation level.

    However, HDAC6 has multiple substrates. To further verify the relationship between microtubule acetylation and Tau toxicity, we mutated lysine at position 40 of endogenous a-tubulin in Drosophila to glutamine to mimic the acetylation status of microtubules. The results indicate that mimicking acetylated microtubules can rescue the developmental abnormalities of microtubules and synapses caused by overexpression of Tau. In addition, after the Drosophila overexpressing Tau develops to a certain stage (second-instar larvae), tubatatin A or ACY-1215, a specific inhibitor of HDAC6, is also added to the food and the microtubule disrupted phenotype can also be partially rescued. Suggesting that increasing microtubule acetylation at a specific time could repair the damaged microtubule network. This study reveals the mechanism by which Tau protein damages microtubules during the pathogenesis of Tau proteinopathy and provides a new idea for the development of drugs for the prevention and treatment of Tau-related diseases.

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