Insights · Scientific

Sydney – one month on!

When I got back from the International Symposium in December, I spent my first few days in the office looking through my notes and reading around them. At the time I felt that it was diversion / procrastination from other things lurking in my In Box. Now, frankly, I wish I’d spent more time on it! Even a month on it’s hard to remember the things I found really exciting. Below are a few subjects that still jump out at me.

Importance of expansions:

Perhaps unsurprisingly, the talk of the symposium was around the recent discovery of the C9orf72 hexanucleotide repeat. Once one repeat sequence was on my mind, I was suddenly noticing all of the others discussed at the meeting!

In his acceptance presentation for his Paulo Gontijo Award, Aaron Gitler described his work in identifying a ‘repeat’ in the coding area of Ataxin 2 which increases the risk of developing ALS. The research was published in Nature in August 2010 . In summary:

People with MND were more likely than healthy controls to have an expansion of between 27-33 glutamine repeats, with an odds ratio of 2.8. People with less than 27 repeats were healthy and had an unchanged risk of developing MND. Repeat lengths of greater than 34 cause a type of ataxia known as SCA2. Participants in Dr Gitler’s study who had this intermediate repeat (4.7% of all cases of MND) had an earlier age of onset of disease than those who did not. On a cellular level: the longer the repeat length, the greater the interaction with TDP43.

Aaron Gitler identified the repeat using a yeast model, designed to measure the level of protein accumulation. Starting from looking at fly genes (with human analogues) that interacted with TDP43, he found that too much of the fly-equivalent of Ataxin2 exacerbates TDP43 toxicity, and lower levels reduced it.

In the eighteen months since this paper was published the link between Ataxin2 and MND has been confirmed in a greater number of patients (in two studies looking at European patients) and wider applications of this yeast model in ALS have been published. (Gispert et al Neurobiology of Disease, 2012; 45(1) 356-361, Lee et al Hum. Mol. Genet. 2011 20(9):1697-1700 and Courthouis et al PNAS 2011, doi 10.1073/pnas.1109434108 respectively. The latter article, on the yeast model, is available through open access).

The latest news of another repeat was presented in the Genetics session of the symposium by Wouter van Rheenan from Utrecht in The Netherlands (Abstract C62 from the meeting). Building on their results of genome scan for copy number variations ( published in 2010 ), he presented some results on their findings of NIPA1. A long (more than 13) polyalanine repeat in the first exon of the gene was found in 2.8% of people with MND compared to 1.8% of controls. Looking in three European populations, a long repeat was significantly associated with disease. Looking at the phenotype of these patients, the presence of a NIPA1 repeat was linked to a shorter survival and an earlier age of onset.

If the hot topic of this year’s symposium was genetic repeats, then the role of RNA biology in MND came a close second.

RNA biology

Every year, in the months leading up to the symposium I promise myself that I’m going to do some preparation – pay more careful attention to the literature, read some reviews etc, – but I’m ashamed to say I never do! One area I feel my knowledge is particularly lacking is in the area of RNA biology. For this reason I approached Session 4A of the symposium ‘RNA and protein processing’ with some trepidation. However, Professor Bob Brown’s excellent opening overview led me in gently. Things I took away with me from this session were: just how many of the disease-causing genes are linked to RNA biology – 6 directly and 2 indirectly, accounting for some 35% of the causes of familial MND; and the all-encompassing role of TDP43 – that it regulates or interacts with a third of all transcriptomes. My appetite has been whetted to get on with some reading after all!

Exchange of Information

The mission statement of the International Symposium is to ‘stimulate improvement in quality of life for people living with ALS/MND, scientific innovation and exchange of information’, wider than this at the MND Association, we have recently developed a position to promote proactive good management and sharing of samples, data and information; as part of the  Association’s research strategy. One area where we are keen for sharing to take place is that of sharing of genetic data, a point that Professor Kevin Talbot alluded to in the closing talk in Sydney, when he stated that “I think all genetic information should be deposited publically” – it was music to my ears!

This year, for the first time there was a ‘Repositories and Resources’ poster session at the meeting, the posters covered the development of a range of resources, from clinical trial data to animal research (Abstract numbers SW195-200). Although presentations have been made on this topic at past symposia, this is the first time that they were collected together.

It is in the spirit of information and data sharing that I’ve tried to reference as much of what I’ve written about in this post as I went along. I’d like to conclude by directing you to a couple more sources of information. Firstly, all of the abstracts are available to download from the MND Association’s website and secondly, there is an extensive non-technical report of the symposium on our research blog.

Happy Reading!