More and more, DNA repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis (ALS). Our DNA contains a complex code to instruct the production of proteins, which are essential to our normal functioning. This DNA code is composed of four different building blocks, called ‘nucleotides’. Repeat expansions happen when a short stretch of nucleotides is erroneously repeated for a number of times. This form of mutation can have serious consequences for the functioning of a protein. So far, several repeat expansions in different genes (C9orf72,  ATXN2 and NIPA1) have been associated with ALS. Using the Project MinE database, a repeat expansion in another gene was discovered that can now be added to this list: ATXN1.

A dedicated team of researchers from the Project MinE partners of the Netherlands (UMCU) and Belgium (UZ Leuven) analysed the genetic profiles of 11,700 individuals. This research team, led by Michael van Es and Philip van Damme, discovered that a repeat expansion in the ATXN1 gene is associated with ALS disease risk. These findings are backed-up by similar observations made previously in an Italian cohort. 

The ATXN1 gene refers to a region in our DNA which contains the instructions to produce the protein ‘ataxin-1’. Proteins are made up of long chains of amino acid molecules. The mutation in the ATXN1 gene was found to result in an ataxin-1 protein containing too many repeats of the amino acid ‘glutamine’. To find out how these glutamine repeats in the ataxin-1 protein could contribute to the development of ALS, the researchers focused on the interaction with another protein: TDP-43. TDP-43 accumulation in the brain is a pathological hallmark of ALS. Subsequent functional experiments showed that expanded ATXN1 contributes to the mislocalisation of the protein TDP-43. Accordingly, increased glutamine repeats in ataxin-1 worsened disease characteristics in fruit fly models of ALS.

Together with previous publications on the ATXN2 gene in ALS, this study adds to the growing evidence that glutamine repeats seem to play an important role in the development of ALS. However, the researchers stress that a repeat expansion in ATXN1 by itself is not a hereditary or causative factor, but an additional risk factor for individuals already at risk for developing the disease due to other genetic and environmental factors. Nonetheless, these results provide interesting leads for further research into the underlying mechanisms causing ALS and could be used to explore new  directions for therapeutic interventions.

The findings of this study have recently been published in the scientific journal Brain Communications