Histone deacetylase 6 interacts with the microtubule-associated protein tau

• Published in: Journal of neurochemistry 2008-09, Vol.106 (5), p.2119-2130
• Main Authors: Ding, Huiping, Dolan, Philip J, Johnson, Gail V.W
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Aged; Alzheimer disease; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Anilides - pharmacology; Biochemistry; Biological and medical sciences; Brain - metabolism; Brain - pathology; Cell Compartmentation - physiology; Cell Line; Cellular biology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Down-Regulation - genetics; Enzyme Inhibitors - pharmacology; Female; Histone Deacetylase 6; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Hydroxamic Acids - pharmacology; Male; Medical sciences; Microtubules - metabolism; Middle Aged; Neurofibrillary Tangles - metabolism; Neurofibrillary Tangles - pathology; Neurology; Neurons - metabolism; Neurons - pathology; Organelles - metabolism; Organic mental disorders. Neuropsychology; phosphorylation; Phosphorylation - drug effects; protein accumulation; Protein Binding - physiology; Protein Structure, Tertiary - physiology; Proteins; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; RNA, Small Interfering - genetics; tau Proteins - metabolism; tubacin; tubulin deacetylation
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05564.x

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.