Abstract
ABSTRACTTau normally associates with and stabilizes microtubules (MTs), but is hyperphosphorylated and aggregated into neurofibrillary tangles in Alzheimer's disease and related neurodegenerative diseases, which are collectively known as tauopathies. MTs are regulated by different forms of post-translational modification, including acetylation; acetylated MTs represent a more stable microtubule population. In our previous study, we showed that inhibition of histone deacetylase 6 (HDAC6), which deacetylates tubulin at lysine 40, rescues defects in MTs and in neuromuscular junction growth caused by tau overexpression. However, HDAC6 also acts on other proteins that are involved in distinct biological processes unrelated to tubulins. In order to examine directly the role of increased tubulin acetylation against tau toxicity, we generated a site-directed α-tubulinK40Q mutation by CRISPR/Cas9 technology to mimic the acetylated MTs and found that acetylation-mimicking α-tubulin rescued tau-induced MT defects and neuromuscular junction developmental abnormalities. We also showed that late administration of ACY-1215 and tubastatin A, two potent and selective inhibitors of HDAC6, rescued the tau-induced MT defects after the abnormalities had already become apparent. Overall, our results indicate that increasing MT acetylation by either genetic manipulations or drugs might be used as potential strategies for intervention in tauopathies.
Highlights
The microtubule-associated protein tau stabilizes microtubules (MTs)
In the brains of Alzheimer’s disease (AD) patients, histone deacetylase 6 (HDAC6) is significantly increased compared with the normal brain, and the tubulin acetylation is reduced in neurons carrying the tau neurofibrillary tangles (Hempen and Brion, 1996)
We previously reported that HDAC6 mutations and inhibitors increase α-tubulin acetylation and rescue the tau toxicity induced by overexpression of tauV337M (Xiong et al, 2013), demonstrating the importance of α-tubulin acetylation in inhibiting tau toxicity
Summary
MTs are regulated by different forms of post-translational modification, including phosphorylation, glutamylation, tyrosination and acetylation. In the brains of AD patients, HDAC6 is significantly increased compared with the normal brain, and the tubulin acetylation is reduced in neurons carrying the tau neurofibrillary tangles (Hempen and Brion, 1996). We previously showed that ectopically expressed human tau in Drosophila results in decreased MT density, increased MT fragments, and more satellite boutons at neuromuscular junctions (NMJs) (Xiong et al, 2013). In Drosophila, HDAC6 regulates the deacetylation of α-tubulin, and we showed that null mutants of HDAC6 attenuate the tau toxicity in Drosophila (Xiong et al, 2013)
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