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Xiong, Y., Zhao, K., Wu, J., Xu, Z., Jin, S., Zhang, Y.Q. (2013). HDAC6 mutations rescue human tau-induced microtubule defects in Drosophila.  Proc. Natl. Acad. Sci. U.S.A. 110(12): 4604--4609.
FlyBase ID
FBrf0221116
Publication Type
Research paper
Abstract

Neurons from the brains of Alzheimer's disease (AD) and related tauopathy patients contain neurofibrillary tangles composed of hyperphosphorylated tau protein. Tau normally stabilizes microtubules (MTs); however, tau hyperphosphorylation leads to loss of this function with consequent MT destabilization and neuronal dysfunction. Accordingly, MT-stabilizing drugs such as paclitaxel and epothilone D have been shown as possible therapies for AD and related tauopathies. However, MT-stabilizing drugs have common side effects such as neuropathy and neutropenia. To find previously undescribed suppressors of tau-induced MT defects, we established a Drosophila model ectopically expressing human tau in muscle cells, which allow for clear visualization of the MT network. Overexpressed tau was hyperphosphorylated and resulted in decreased MT density and greater fragmentation, consistent with previous reports in AD patients and mouse models. From a genetic screen, we found that a histone deacetylase 6 (HDAC6) null mutation rescued tau-induced MT defects in both muscles and neurons. Genetic and pharmacological inhibition of the tubulin-specific deacetylase activity of HDAC6 indicates that the rescue effect may be mediated by increased MT acetylation. These findings reveal HDAC6 as a unique potential drug target for AD and related tauopathies.

PubMed ID
PubMed Central ID
PMC3606981 (PMC) (EuropePMC)
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    Language of Publication
    English
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    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Proc. Natl. Acad. Sci. U.S.A.
    Title
    Proceedings of the National Academy of Sciences of the United States of America
    Publication Year
    1915-
    ISBN/ISSN
    0027-8424
    Data From Reference
    Aberrations (1)
    Alleles (9)
    Genes (5)
    Human Disease Models (1)
    Natural transposons (1)
    Insertions (1)
    Experimental Tools (1)
    Transgenic Constructs (7)