PMID- 25209898
OWN - NLM
STAT- MEDLINE
DCOM- 20150908
LR  - 20211021
IS  - 1432-1440 (Electronic)
IS  - 0946-2716 (Linking)
VI  - 93
IP  - 1
DP  - 2015 Jan
TI  - MeCP2 deficiency is associated with reduced levels of tubulin acetylation and can 
      be restored using HDAC6 inhibitors.
PG  - 63-72
LID - 10.1007/s00109-014-1202-x [doi]
AB  - Rett syndrome (RTT) is a severe neurodevelopmental disorder, predominantly caused 
      by loss of function mutations in the X-linked methyl-CpG-binding protein 2 
      (MECP2) gene. Despite the genetic cause being known in the majority of cases, the 
      pathophysiology of the neurological phenotype of RTT is largely unknown. Tubulin 
      and the microtubule network play an essential role in neuronal function whereby 
      the acetylation state of microtubules dictates the efficiency of neuronal 
      migration and differentiation, synaptic targeting and molecular motor trafficking 
      of mRNA, high-energy mitochondria and brain-derived neurotrophic factor 
      (BDNF)-containing vesicles. Recent reports have shown perturbations in tubulin 
      and microtubule dynamics in MeCP2-deficient cells, suggesting a link between the 
      aberrations of these cellular entities and the neurobiology of RTT. We have 
      interrogated the functional state of the microtubule network in fibroblasts 
      derived from two patients with RTT as well as cortical neurons from a RTT mouse 
      model and observed a reduction in acetylated alpha-tubulin and an increase in the 
      tubulin-specific deacetylase, histone deacetylase 6 (HDAC6). Furthermore, we show 
      that inhibition of HDAC6 by Tubastatin A can restore tubulin acetylation levels. 
      We also demonstrate microtubule instability in the RTT patient fibroblasts in 
      response to nocodazole, which is progressively ameliorated in a 
      mutation-dependent manner by Tubastatin A. We conclude that Tubastatin A is 
      capable of counteracting the microtubule defects observed in MeCP2-deficient 
      cells, which could in turn lead to the restoration of molecular trafficking along 
      the microtubules and thus could be a potentially new therapeutic option for RTT. 
      KEY MESSAGE: Cells from MeCP2-deficient cells show reduced levels of acetylated 
      alpha-tubulin. Cells from two patients and a RTT mouse model have increased levels of 
      HDAC6 but not sirtuin 2 (SIRT2). Inhibition of HDAC6 by Tubastatin A increases 
      the in vitro acetylation of alpha-tubulin. Inhibition of HDAC6 by Tubastatin A does 
      not increase MECP2 expression. Cells from two patients show microtubule 
      instability, which is ameliorated by Tubastatin A.
FAU - Gold, W A
AU  - Gold WA
AD  - NSW Centre for Rett Syndrome Research, Western Sydney Genetics Program, The 
      Children's Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, New South 
      Wales, 2145, Australia.
FAU - Lacina, T A
AU  - Lacina TA
FAU - Cantrill, L C
AU  - Cantrill LC
FAU - Christodoulou, John
AU  - Christodoulou J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140912
PL  - Germany
TA  - J Mol Med (Berl)
JT  - Journal of molecular medicine (Berlin, Germany)
JID - 9504370
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (Hydroxamic Acids)
RN  - 0 (Indoles)
RN  - 0 (Methyl-CpG-Binding Protein 2)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tubulin)
RN  - 2XTSOX1NF8 (tubastatin A)
RN  - EC 3.5.1.98 (Hdac6 protein, mouse)
RN  - EC 3.5.1.98 (Histone Deacetylase 6)
RN  - EC 3.5.1.98 (Histone Deacetylases)
SB  - IM
MH  - Acetylation
MH  - Animals
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Fibroblasts/*drug effects/metabolism
MH  - Gene Expression/drug effects
MH  - Histone Deacetylase 6
MH  - Histone Deacetylase Inhibitors/*pharmacology
MH  - Histone Deacetylases/*metabolism
MH  - Humans
MH  - Hydroxamic Acids/*pharmacology
MH  - Indoles/*pharmacology
MH  - Male
MH  - Methyl-CpG-Binding Protein 2/genetics/*metabolism
MH  - Mice, Transgenic
MH  - Microtubules/drug effects/metabolism
MH  - Mutation
MH  - RNA, Messenger/metabolism
MH  - Rett Syndrome/genetics/metabolism
MH  - Tubulin/*metabolism
EDAT- 2014/09/12 06:00
MHDA- 2015/09/09 06:00
CRDT- 2014/09/12 06:00
PHST- 2014/03/02 00:00 [received]
PHST- 2014/08/14 00:00 [accepted]
PHST- 2014/07/13 00:00 [revised]
PHST- 2014/09/12 06:00 [entrez]
PHST- 2014/09/12 06:00 [pubmed]
PHST- 2015/09/09 06:00 [medline]
AID - 10.1007/s00109-014-1202-x [doi]
PST - ppublish
SO  - J Mol Med (Berl). 2015 Jan;93(1):63-72. doi: 10.1007/s00109-014-1202-x. Epub 2014 
      Sep 12.