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

Content Provider	Springer Nature Link
Author	Gold, W. A. Lacina, T. A. Cantrill, L. C. Christodoulou, John
Copyright Year	2014
Abstract	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. 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.
Starting Page	63
Ending Page	72
Page Count	10
File Format	PDF
ISSN	09462716
Journal	Journal of Molecular Medicine
Volume Number	93
Issue Number	1
e-ISSN	14321440
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2014-09-12
Publisher Place	Berlin/Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Rett syndrome MECP2 HDAC6 inhibitor Tubastatin A Microtubules Tubulin Molecular Medicine Human Genetics Internal Medicine
Content Type	Text
Resource Type	Article
Subject	Drug Discovery Molecular Medicine Genetics (clinical)

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