HDAC6 inhibition results in tau acetylation and modulates tau phosphorylation and degradation in oligodendrocytes.
Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family. It is localized within the cytoplasm and has unique substrate specificities for nonhistone proteins, such as α-tubulin. Furthermore, it plays a major role in protein aggregate formation and recently was demonstrated to interact with the microtubule associated protein tau and tau was identified as a possible substrate for HDAC6 in neurons. This study was undertaken to investigate whether HDAC6 is present in oligodendrocytes and whether it is involved in tubulin and tau acetylation in these cells. We show for the first time that HDAC6 is expressed in cultured rat brain oligodendrocytes. Its inhibition by the specific HDAC6 inhibitor tubastatin A (TST) leads to morphological alterations, microtubule bundling, and tubulin acetylation, and changes in tau-isoform expression and phosphorylation. Furthermore, the microtubule binding activity of tau was reduced. Using the oligodendroglial cell lines OLN-t40 and OLN-t44, which were genetically engineered to express either the longest human tau isoform with four microtubule binding repeats (4R-tau), or the shortest tau isoform with three repeats (3R-tau), respectively, we demonstrate that tau is acetylated by HDAC6 within the 4R-binding domain. Tau acetylation reduced its turnover rate and acetylated tau was degraded slower in these cells. TST and shRNA-mediated knockdown of HDAC6 in oligodendroglia cells caused an increase in pathological hyperphosphorylated tau detectable with the 12E8 antibody. Hence HDAC6 and dysregulation of the deacetylation and acetylation process in oligodendrocytes may contribute to diseases with oligodendroglial pathology.
Department of Biology, Molecular Neurobiology, University of Oldenburg, D-26111, Oldenburg, Germany.
Monika
M
Noack
Janina
J
Leyk
Christiane
C
Richter-Landsberg
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008870:Microtubules / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014404:Tubulin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D034741:RNA, Small Interfering; D014404:Tubulin; D016875:tau Proteins; C553587:tubastatin A; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
glial cells; microtubules; tau isoform expression; tauopathy; tubastatin; tubulin acetylation