Thursday, 13 October 2011

Caspase the executioner

The very dramatic title to this post pays homage to the caspases and their role in the process of programmed cell death (apoptosis). Their 'executioner' label denotes their role in the cascade effect that ends the life of a cell. If, like me, you watch too many films and documentaries about Medieval England (don't we all?), you might picture the executioner as a hangman, face covered, being paid to go about his duties. Grim stuff indeed.

Enough of all that. Like many things connected to our very complicated human biology, the protease family known as the caspases are also involved in other processes outside of just cell death. One of these processes is inflammation and partially mediating inflammatory functions such as those linked to autoimmunity.

A recent paper by Siniscalco and colleagues* sheds some light on a possible role for the caspases in connection to autism spectrum conditions. There was always going to be some interest for me in this paper given the authorship group. When names like Laura de Magistris (she of the leaky gut) and Alessio Fasano appear, I tend to sit up and take note. Please don't take this as any kind of idol-worshipping or anything like that; merely some admiration for their collected works; sort of winners of an X-Factor for scientists (now there's a novel idea).

Anyway, I mentioned that the caspases are a group of enzymes with quite a few members. Within the family, various caspases have various different duties and show various different effects when things aren't quite as they should be. The crux of the current paper was to demonstrate whether caspase expression (mRNA and protein levels) were different in a small group of children diagnosed with autism compared with controls.

The answer bearing in mind the ever-so-small numbers included for study was yes, levels were different; and different across a few of the caspases. The messenger RNA (mRNA) levels were increased for caspases-1, -2, -4. -5. Caspases-1, -4, and -5 are important because of their connection with inflammation. Important also because the caspases need to work synergistically together in order to have their 'full activity'. When protein levels of the caspases were measured, caspases-3, -7, -12 were found to be elevated in the autistic group. Caspase-3, when activated, for example seems to play a role in neurodegenerative conditions such as Alzheimer's disease (AD) and its connection with the amyloid beta precursor protein (APP). The effect is described as an enhancing one, in that caspase-3 is in the thick of all those tangles and plaques noted in AD. Caspase-12 takes us back to inflammation and caspase-7 back to apoptosis.

Cumulatively, the various caspases examined and reported on, seem to imply inflammation and a role for the immune system in the cases studied. I am a bit baffled by the caspase-3 finding in light of the connection to AD in other work, which perhaps contrasts with what is known about APP and those wretched peptides in relation to autism. Having said that, I do realise that AD is a very complicated condition and the presence of caspase-3 may reflect other processes. So how about a possible link between caspase-3 and type-1 diabetes instead?

This is not the first time that the caspase family have appeared on the autism research landscape. Mady Hornig and colleagues (she of the recent carbohydrate metabolism paper) discussed caspase-1 in relation to apoptosis and neurodevelopmental damage in this paper from a few years back. This paper by Sheikh and colleagues reported caspase-3 as being a more direct marker of apoptosis being elevated in the cerebellum portion of the brains of people with autism. Cerebellum, autism, Eric Courchesne?

The caspases are an interesting family of enzymes, of that there is no doubt. Further large-scale trials are needed to confirm findings and subsequently to start thinking about when, how and why the caspase findings become relevant to autism and what can be done to modify any detrimental effects.

To forget all this talk about executioners, how about Huey and some News?

Siniscalco D. et al. The expression of caspases is enhanced in peripheral blood mononuclear cells of autism spectrum disorder patients. JADD. October 2011.