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Histone deacetylase 6 (HDAC6), a unique cytoplasmic deacetylase, likely plays a role in neurodegeneration by coordinating cell responses to abnormal protein aggregation. Here, we provide in vitro and in vivo evidence that HDAC6 interacts with tau, a microtubule-associated protein that forms neurofibrillary tangles in Alzheimer's disease. This interaction is mediated by the microtubule-binding domain on tau and the Ser/Glu tetradecapeptide domain on HDAC6. Treatment with tubacin, a selective inhibitor of tubulin deacetylation activity of HDAC6, did not disrupt HDAC6–tau interaction. Nonetheless tubacin treatment attenuated site-specific tau phosphorylation, as did shRNA-mediated knockdown of HDAC6. Proteasome inhibition potentiated HDAC6–tau interactions and facilitated the concentration and co-localization of HDAC6 and tau in a perinuclear aggresome-like compartment, independent of HDAC6 tubulin deacetylase activity. Furthermore, we observed that in Alzheimer's disease brains the protein level of HDAC6 was significantly increased. These findings establish HDAC6 as a tau-interacting protein and as a potential modulator of tau phosphorylation and accumulation. 相似文献
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Qian Cheng Eric Balzer Stephen M. Miller Minoru Yoshida Jason C. Wong 《Journal of phycology》2006,42(2):417-422
Volvox carteri f. nagariensis (Iyengar) possesses several thousand cells of just two types, gonida and somatic cells, that are set apart by asymmetric cell division. Because the division apparatus contains microtubules enriched in acetylated α‐tubulin, we wished to know whether acetylated tubulin plays any role in regulating division symmetry. Two different human histone deacetylases (HDACs) have been shown to deacetylate tubulin in vivo, thereby regulating cell motility. Here we set out to determine: (1) whether HDAC inhibitors that increase tubulin acetylation in animal cells have the same effect in V. carteri, (2) whether increasing acetylated tubulin affects microtubule stability, and (3) whether increasing acetylated tubulin affects division symmetry. Embryos exposed to two HDAC inhibitors, trichostatin A (TSA) and tubacin, accrued dramatically higher levels of acetylated tubulin (and more acetylated microtubules) and were significantly more sensitive to colchicine than controls. However, while TSA‐treated embryos cleaved aberrantly to produce adults with abnormal morphology, tubacin‐treated embryos developed normally. We conclude that increasing tubulin acetylation subtly alters microtubule stability, but does not appear to affect cell division in V. carteri. 相似文献
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Pharmacologically increasing microtubule acetylation corrects stress‐exacerbated effects of organophosphates on neurons
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Zachary D. Brodnik Liang Qiang Rodrigo A. España Kimberly A. Sullivan Mark M. Black Peter W. Baas 《Traffic (Copenhagen, Denmark)》2017,18(7):433-441
Many veterans of the 1990‐1991 Gulf War contracted Gulf War Illness (GWI), a multisymptom disease that primarily affects the nervous system. Here, we treated cultures of human or rat neurons with diisopropyl fluorophosphate (DFP), an analog of sarin, one of the organophosphate (OP) toxicants to which the military veterans were exposed. All observed cellular defects produced by DFP were exacerbated by pretreatment with corticosterone or cortisol, which, in rat and human neurons, respectively, serves in our experiments to mimic the physical stress endured by soldiers during the war. To best mimic the disease, DFP was used below the level needed to inhibit acetylcholinesterase. We observed a diminution in the ratio of acetylated to total tubulin that was correctable by treatment with tubacin, a drug that inhibits HDAC6, the tubulin deacetylase. The reduction in microtubule acetylation was coupled with deficits in microtubule dynamics, which were correctable by HDAC6 inhibition. Deficits in mitochondrial transport and dopamine release were also improved by tubacin. Thus, various negative effects of the toxicant/stress exposures were at least partially correctable by restoring microtubule acetylation to a more normal status. Such an approach may have therapeutic benefit for individuals suffering from GWI or other neurological disorders linked to OP exposure. 相似文献
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