Journal of Molecular Medicine

, Volume 93, Issue 1, pp 63–72 | Cite as

MeCP2 deficiency is associated with reduced levels of tubulin acetylation and can be restored using HDAC6 inhibitors

  • W. A. Gold
  • T. A. Lacina
  • L. C. Cantrill
  • John ChristodoulouEmail author
Original Article


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 α-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 α-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 α-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.


Rett syndrome MECP2 HDAC6 inhibitor Tubastatin A Microtubules Tubulin 



We thank Associate Professor James Eubanks of the University of Toronto, for many valuable discussions and Dr Zhaolan Zhou of the University of Pennsylvania, for supplying us with the initial breeding stock of the Mecp2 T158A mouse model. This work was supported by the Rett Syndrome Association of New South Wales, Rett Syndrome Australian Research Fund, Rett Syndrome Association of Australia, International Rett Syndrome Foundation and Shire Human Genetic Therapies Inc (Lexington, MA, USA).

Conflict of interest

The authors declare that there are no commercial or other conflicts of interest in connection with this research.

Supplementary material

109_2014_1202_MOESM1_ESM.pdf (154 kb)
Supplementary Table S1 Statistical analysis for Fig. 4 (Tubastatin A protects microtubules from severe nocodazole-induced depolymerisation). Statistical analysis was conducted on the computational counts of relative intensity levels of polymerised microtubules of patient and control fibroblasts treated in Fig. 4. (PDF 153 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • W. A. Gold
    • 1
    • 2
  • T. A. Lacina
    • 3
  • L. C. Cantrill
    • 2
    • 4
  • John Christodoulou
    • 1
    • 2
    • 5
    Email author
  1. 1.NSW Centre for Rett Syndrome Research, Western Sydney Genetics ProgramThe Children’s Hospital at WestmeadSydneyAustralia
  2. 2.Discipline of Paediatrics & Child HealthUniversity of SydneySydneyAustralia
  3. 3.Faculty of BiotechnologyHochschule Mannheim (University of Applied Sciences)MannheimGermany
  4. 4.Microscope Facility, Kids Research InstituteThe Children’s Hospital at WestmeadSydneyAustralia
  5. 5.Discipline of Genetic Medicine, Sydney Medical SchoolUniversity of SydneySydneyAustralia

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