Tuesday, 12 June 2012

mTOR and autism

Now don't be put off by the title of this post or the 'jargon' that follows but I want to talk about something called mTOR. I know, I know, it sounds like Godzilla's cousin but it's not; it might actually be a whole lot more important than that.

mTOR aka the mammalian target of rapamycin has been cropping up quite frequently during my various searches of the research literature. I was intrigued by the name of this ubiquitous protein kinase which apparently is involved in all manner of things including protein synthesis and synaptic plasticity. Some interesting findings in relation to depression and the mTOR signalling pathway have been reported but it might not end there.

I don't want to blind you with science - science which I am barely coming to grips with myself - but important parts of the mTOR story are the complexes: mTOR complex 1 (mTORC1) and complex 2 (mTORC2) whereby mTOR holds hands with other proteins and heads off into slightly different functioning directions. This paper by Laplante & Sabatini* (full-text) is about a good an overview of the different complexes as you are likely to find.

When it comes to autism, mTOR seems to be of increasing interest, having had quite a surprising journey. As far as I can make out, it all started with some interesting work on tuberous sclerosis, a genetic condition defined by the presence of benign, non-cancerous tumours in different parts of the body, but also potentially presenting with autism or autistic-like behaviours. Meikle and colleagues** (full-text) described some preliminary findings based on the inhibition of mTORC1 by rapamycin and an interestingly titled compound called RAD001. These quite potent immuno-suppressive compounds more frequently used to counteract organ rejection after transplant, seemed to have quite an effect on survival rates and a few other areas at least in the mouse model. This work was extended to cover some of the behavioural and learning disabilities, again in the mouse model of tuberous sclerosis*** (full-text).

The more recent research on mTOR seems to be more directed to autism outside of just the tuberous sclerosis and Fragile X syndrome link. The paper by Ehninger & Silva**** (full-text) summed up the potential use of rapamycin in relation to a subset of cases of autism spectrum conditions and the paper by Talos and colleagues***** (full-text) brings us up to date with their suggestion that mTOR might show some link to autism and epilepsy via that most interesting of amino acids, glutamate and onwards glutamingeric transmission. I might add that I am in no way endorsing the use of rapamycin or anything else for autism.

Even this year's IMFAR conference carried mention of mTOR and autism as per these three abstracts: here, here and here. Again I don't profess to be the wise old sage when it comes to these findings but am interested in a few aspects of these works in relation to annexin 1 (and its anti-inflammatory effects) and the whole brain-derived neutrophic factor (BDNF) story which in the case of autism, probably deserves a post of its own at some point.

There is still a way to go with the mTOR pathway and indeed how pertinent it might be to cases of autism and other conditions as per its cellular growth and proliferation duties. That and its ability to direct immune responses as per the review by Delgoffe & Powell****** (full-text) represents a work in progress.

In the words of the great Ferris Bueller, 'you're still here'. Well if you are, how about some music courtesy of Blondie and possibly their best song... Atomic as memories of Obi-Wan's other acting performances come to mind.

* Laplante M. & Sabatini DM. mTOR signalling at a glance. Journal of Cell Science. 2009; 122: 3589-3594.

** Meikle L. et al. Response of a neuronal model of tuberous sclerosis to mTOR inhibitors. The Journal of Neuroscience. 2008; 28: 5422-5432.

*** Ehninger D. et al. Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nature Medicine. 2008; 14: 843-848.

**** Ehninger D. & Silva AJ. Rapamycin for treating Tuberous sclerosis and Autism spectrum disorders. Trends in Molecular Medicine. 2011; 17: 78-87.

***** Talos DM. et al. The interaction between early life epilepsy and autistic-like behavioral consequences: a role for the mammalian target of rapamycin (mTOR) pathway. PLoS ONE. 2012; 7: e35885

****** Delgoffe GM. & Powell JD. mTOR: taking cues from the immune microenvironment. Immunology. 2009; 127: 459-465