Wednesday, 16 April 2014

Joined by HDAC (inhibitors)

I'm treading quite carefully with this post which came about following my [non-expert] reading of the paper abstract from Anand Venkatraman and colleagues [1] on a potential downside to the use of HDAC (histone deacetylase) inhibitors for treating spinocerebellar ataxia type 1 (SCA1), a progressive disease affecting movement and other knock-on functions. This follows other work suggesting that certain HDAC inhibitors might offer some important new lines of investigation when it comes to at least some of the various types of spinocerebellar ataxia (SCA). For those who thought this was a blog about autism research, bear with me on this one...

HDACs represent a group of enzymes which go to work removing acetyl groups on histone tails which, as the paper by Patrick Grant [2] (open-access) very nicely illustrates, has the potential to do some rather important things to processes like gene expression (condensing chromatin and repressing transcription). I have kinda touched upon histones and the so-called histone code in a previous introductory post on the rise and rise of epigenetics (see here) with autism in mind.

The Venkatraman results focused on a mouse model, and how depletion/loss of a particular type of HDAC - HDAC3 - was in some cases: "highly deleterious both behaviorally, with mice showing early onset ataxia, and pathologically, with progressive histologic evidence of degeneration". They talk about "cautionary evidence that this approach could produce untoward effects" when it comes to the employment of "pharmacologic inhibition of HDAC3" via HDAC inhibitors in SCA.

Not to make too many sweeping generalisations or form associations which might not be there, but two things from the Venkatraman paper got my old(ish) grey matter fired up: (i) mention of HDAC inhibitors and the emerging story when it comes to prenatal exposure to valproate with a HDAC slant, and (ii) the focus on Purkinje cell function; as their paper title states: "The histone deacetylase HDAC3 is essential for Purkinje cell function". Both these points bring me back to some potentially important issues which might apply to at least some autism and related neurodevelopmental outcomes.

It is still very much an emerging picture but pregnancy use of valproate and 'adverse' offspring events/development is turning into something of a quite important association in recent times. So much so that the US FDA and UK MHRA have issued some guidance on this matter. Valproate has some history as a potential teratogen [3] bearing in mind my offering no medical or clinical advice on this matter aside from saying 'don't mess with epilepsy'. That valproate is also an HDAC inhibitor [4] (open-access) is another mechanism through which the drug might (a) find some new markets for conditions other than epilepsy, but also (b) impact on development and functions. Readers are invited to have a look through the paper by Katie Lloyd [5] (open-access) for a well-rounded overview of potential effects.

Then to the Purkinje cell story. I'm sure most people with an interest in autism will have heard about the cerebellum in relation to the condition at some point. Indeed, the paper by Fatemi and colleagues [6] (open-access) kinda sums up where we're at when it comes to the 'little brain' bearing in mind the need for further investigation and the greater focus on the plural 'autisms'. To talk about the cerebellum and autism also brings into the play those Purkinje cells which have also featured on several occasions on the autism research menu [7] and quite recently, with an epigenetic slant to the research (see here). Indeed, the paper by Jill James and colleagues [8] (open-access) on epigenetics and EN-2 is something I'd very much like to see more work on.

Again, not to make mountains out of molehills, but I did wonder whether there may be some science to do covering these potentially overlapping areas. I'm not necessarily saying that valproate = HDAC inhibition = impact on Purkinje cell numbers/maturation/functions = autism because I very much doubt it's going to be that simple or generalised despite some emerging [rodent] data [9]. With the increasing interest in all-things epigenetic however, also crossing over to autism research [10] (open-access), one might consider more inquiry into the HDACs, their inhibitors and effectors (and exposure timing) to be a potentially important part of that particular autism research tide? Whether even important ecosystems e.g. "the [gut] microbiota itself may be viewed as an epigenetic entity" [11] may also tie into some of the work in this area too?

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[1] Venkatraman A. et al. The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1. Hum Mol Genet. 2014 Mar 4.

[2] Grant PA. A tale of histone modifications. Genome Biology 2001, 2:reviews0003-reviews0003.6

[3] Alsdorf R. & Wyszynski DF. Teratogenicity of sodium valproate. Expert Opin Drug Saf. 2005 Mar;4(2):345-53.

[4] Göttlicher M. et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001; 20(24): 6969–6978.

[5] Lloyd KA. A scientific review: mechanisms of valproate-mediated teratogenesis. Bioscience Horizons 2013; 6 : hzt003

[6] Fatemi SH. et al. Consensus paper: pathological role of the cerebellum in autism. Cerebellum. 2012 Sep;11(3):777-807.

[7] Skefos J. et al. Regional alterations in purkinje cell density in patients with autism. PLoS One. 2014 Feb 24;9(2):e81255.

[8] James SJ. et al. Complex epigenetic regulation of engrailed-2 (EN-2) homeobox gene in the autism cerebellum. Transl Psychiatry. 2013 Feb 19;3:e232.

[9] Moldrich RX. et al. Inhibition of histone deacetylase in utero causes sociability deficits in postnatal mice. Behav Brain Res. 2013 Nov 15;257:253-64.

[10] Lasalle JM. Autism genes keep turning up chromatin. OA Autism. 2013 Jun 19;1(2):14.

[11] Stilling RM. et al. Microbial genes, brain & behaviour - epigenetic regulation of the gut-brain axis. Genes Brain Behav. 2014 Jan;13(1):69-86.

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ResearchBlogging.org Venkatraman A, Hu YS, Didonna A, Cvetanovic M, Krbanjevic A, Bilesimo P, & Opal P (2014). The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1. Human molecular genetics PMID: 24594842