Sunday, 25 November 2012

Matrix metalloproteinases and autism

Peptidases. The enzymes that split apart peptide bonds, have always been of some interest to me. Not only resulting from my continued interest in peptides as being one potential suggestion why a gluten- and/or casein-free diet might affect symptom presentation in some cases of autism but also because of their relationship to the building blocks of functional life, the amino acids, which are really starting to make some waves in autism research.
Just split @ Wikipedia  

With all this in mind, it was perhaps inevitable that I would arrive at a post on a specific class of peptidases, the matrix metalloproteinases (MMPs) and some very preliminary suggestions of potential involvement in cases of autism and beyond. Please note that not all peptidases work on the same types of peptides, just in case you wondered.

It was the paper by Abdallah and colleagues* which spurred me into writing this post, and their suggestion that analysis of amniotic fluid samples indicated that levels of MMP-9 were elevated in cases later diagnosed with an autism spectrum disorder (ASD). The fact that they also mentioned BDNF was a bonus interest.

Perhaps I should back up a little and provide a quick overview of the MMPs. So with my Twitter limit: zinc-dependent, embryonic development, removal of extracellular matrix, immune function and inflammation, synaptic plasticity**, etc. There are a number of very good review articles on the MMPs including this one by Birkedal-Hansen and colleagues*** (open-access).

The specific MMP discussed by Abdallah et al, MMP-9, has been the topic of quite a lot of research interest over the years. The degradation of collagen is an obvious starting point for all the MMPs, hence a link with connective tissue disorders such as rheumatoid arthritis**** (open-access). It is however with the brain and various neuropsychiatric conditions in mind, that I find myself drawn to the potential effects of MMP-9.

Domenici and colleagues***** (open-access) for example, reported on the possibility that elevated plasma MMP-9 levels may (alongside other compounds) be a biomarker for depression in their cohort. Indeed the genetics of MMP-9 have been similarly linked to bipolar and related disorders. There remains however the chicken-and-egg situation of which came first, MMP-9 or symptoms, not really answered by studies such as this one by Rybakowski and colleagues****** relying on MMP-9 levels to predict staging of bipolar disorder.

Outside of the Abdallah study, there is not presently a great wealth of research done on the MMPs with autism in mind. Accepting the fact that Abdallah was looking in amniotic fluids samples and therefore not functional levels per se, I did turn up this paper by Siller and Broadie******* (open-access) looking at MMPs in Fragile X syndrome (FXS). Regular readers might remember a few papers discussed on this blog in recent times with FXS as the target condition (see here and here) presenting with autistic features. Siller and Broadie asked whether administration of the antibiotic minocycline might actually serve to inhibit MMP (activity or formation?). The answer: it might as per other work in this area but please note that this is not to be construed as medical advice.

I was likewise interested to read the paper by Jang and colleagues******** on how everyone's favourite sleeping aid, melatonin, might also have some important effects on MMP-9 levels, at least in a rat model of stroke. That and the possibility(!) that this relationship might also involve blood-brain barrier (BBB) disruption really got the grey matter working. Once again a pharmacological effect that you won't see on the drug packaging insert.

We have yet to see all there potentially is about MMPs with autism in mind. With all the current interest in excitotoxicity in cases of autism linked to things like glutamate and compounded by the whole microglia story, I'm sure it is a topic that will gain in research popularity and perhaps even open up new avenues for intervention********* for specific people and/or groups should perturbed levels be found and replicated. Given also the possibility of a viral link to elevations in MMP9********** one has to assume that environment may also play a hand in some presentations and potentially tie into those models of maternal infection as being a risk factor for offspring autism?

To finish, the King at his best...


* Abdallah MW. et al. Amniotic fluid MMP-9 and neurotrophins in autism spectrum disorders: an exploratory study. Autism Res. September 2012.

** Huntley GW. Synaptic circuit remodelling by matrix metalloproteinases in health and disease. Nature Reviews Neuroscience. 2012; 13: 743-757.

*** Birkedal-Hansen H. et al. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med. 1993 ;4: 197-250.

**** Distler JHW. et al. The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts stimulated with immune cell microparticles. PNAS. 2005; 102: 2892-2897.

***** Domenici E. et al. Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections. PLoS One. 2010; 5: e9166.

****** Rybakowski JK. et al. Increased serum matrix metalloproteinase-9 (MMP-9) levels in young patients during bipolar depression. J Affect Disord. August 2012.

******* Siller SS. & Broadie K. Matrix metalloproteinases and minocycline: therapeutic avenues for fragile X syndrome. Neural Plast. 2012: 124548

******** Jang JW. et al. Melatonin reduced the elevated matrix metalloproteinase-9 level in a rat photothrombotic stroke model. J Neurol Sci. 2012. pii: S0022-510X(12)00524-2

********* Leonardo CC. & Pennypacker KR. Neuroinflammation and MMPs: potential therapeutic targets in neonatal hypoxic-ischemic injury. J Neuroinflammation. 2009; 6: 13.

********** Kolb SA. et al. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in viral meningitis: upregulation of MMP-9 and TIMP-1 in cerebrospinal fluid. J Neuroimmunol. 1998; 84: 143-150.

--------- Abdallah MW, Pearce BD, Larsen N, Greaves-Lord K, Nørgaard-Pedersen B, Hougaard DM, Mortensen EL, & Grove J (2012). Amniotic Fluid MMP-9 and Neurotrophins in Autism Spectrum Disorders: An Exploratory Study. Autism research : official journal of the International Society for Autism Research PMID: 23008271