Tuesday 11 October 2011

Progranulin and autism

I have forgotten the number of times that autoimmunity has been discussed in connection to autism spectrum conditions on this blog. I wouldn't say that I am obsessed with the topic; just quietly interested in how the lack of recognition of self, immunologically-speaking, seems to crop up time and time again in at least some cases of autism alongside the subsequent link to inflammation. I offer no opinion on the implications of such findings, and how 'universal' they might be to the autistic spectrum, but they certainly make for some interesting reading. Just in case you need some more discussion on this topic I present this paper (full-text) by Al-Ayadhi and Mostafa* on the the findings of low plasma progranulin levels in children with autism.

As previously mentioned, the amount of research coming out of the Saudi Arabia on autism has been thick and fast this year with some pretty novel associations being suggested. I note that they have even started to look at that most unusually named of compounds, Sonic Hedgehog Protein in relation to oxidative stress (here); fodder for a separate post methinks. The current paper on progranulin levels continues their research theme on the immune system and inflammation where previous observations have linked things like anti-ganglioside M1 auto-antibodies to some cases of autism.

A little bit of description might be useful to start with on what exactly progranulin is and why it might be important. The technical stuff about progranulin is here, but in as few words as possible: the granulins are a family of leukocyte polypeptides, some of which have cell growth modulatory activity, hence their suggested role in lots of things from wound healing to the creation of cancers. This paper suggested that levels of the source protein progranulin, might also serve as a marker for some of the components of metabolic syndrome but that's all I will say on that particular issue for now.

For the purpose of the current study, progranulin was examined in the context of being an anti-inflammatory neurotrophic factor with neuroprotective qualities. A few other details about the study and findings:

  • Forty children with autism participated in the trial, all medication-free. Forty control children were also used as comparators matched for age and gender and free of any immunological condition.
  • CARS was used to assess the 'level' of autistic behaviours in the experimental group; where levels of plasma progranulin were assessed in all participants.
  • Children with autism had significantly lower levels of plasma progranulin (p=0.001) although there did not appear to be any link with symptom severity as judged by CARS scores, age or gender. Sixty-five percent of children with autism had reduced progranulin levels. It is interesting to note the surprising degree of 'homogeneity' of results from the autistic group compared with controls in terms of the dispersion of individual measured levels. 

These are interesting results allowing for the small participant group examined. The authors discuss the possible relevance of their findings and that too makes for some interesting reading particular when you would expect progranulin levels to be elevated if inflammation was present as some of the literature seems to indicate inflammation is in cases of autism. Does this mean that inflammation might not be present? I don't know but then an awful lot of other results must be wrong. Does this mean that genetically there might be 'glitches' in the pathways required to make progranulin in autism in response to inflammation? I don't know either but no data on this measure seems to exist at the moment. Looking at one parameter alone and in isolation does not tend to provide a very complete picture hence the need for further investigations.

As per the authors comments on the current paper, much more research is required in what is a novel area of investigation. Knockout mice model studies, where the gene for progranulin located on chromosome 17q21 (ring any bells?) is absent, have suggested some male-dependent behaviours potentially linked to the serotonergic system, bearing in mind mice are not necessarily the same as people. A small (very small) suggestion that some cases of schizophrenia might also be linked to mutations in the progranulin gene should also be noted. The Saudi authors discuss the possibility of progranulin therapy in cases of autism but I would be hesitant at best to support such a claim at the moment without lots and lots and lots more research being done on safety and the appropriate dosing.

* Al-Ayadhi LY & Mostafa GA. Low plasma progranulin levels in children with autism. Journal of Neuroinflammation. September 2011.


  1. Hi Paul Whiteley -

    One of my pubmed alerts lit up this morning regarding proganulin (Exacerbated Inflammatory Responses Related to Activated Microglia after Traumatic Brain Injury in Progranulin-Deficient Mice), but then I started poking around related links and ran into something interesting.

    Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. was published in 2010. Here is a snipet from their abstract. [great looking paper, btw!]

    FTD associated with PGRN insufficiency may result from many years of reduced neutrotrophic support together with cumulative damage in association with dysregulated inflammation

    Now, compare that with the abstract from Low plasma progranulin levels in children with autism, published in 2011.

    Progranulin insufficiency in some patients with autism may result in many years of reduced neutrotrophic support together with cumulative damage in association with dysregulated inflammation

    It's just like I always say, 'You gotta watch out for those Egyptians!'

    On the worse side, having decreased progranulin appears to predispose to a variety of neuroinflammatory profiles that you'd rather not have, as opposed to have.

    - pD

  2. Thanks pD.

    They are mighty similar sentences it has to be said....

    Progranulin is still a bit of a mystery to me insofar as the whole elevations of the stuff being linked to inflammation and indeed the potential tie-up with things like microglia:


    I suppose one could assume some kind of bell-shaped dose-response curve to having either lower or higher levels of the stuff as being important, but certainly I'd like to see more work in this area...


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