ANXA11 – another gene closer to understanding ALS

A new research paper has been published today in the Science Translational Medicine journal, describing a new gene implicated in developing MND. What is this gene and why is it important for our fight against MND?

Although they are not the sole cause of MND, genes play a big role in someone’s probability of developing the disease. A number of such genes that make a person susceptible to developing MND have already been identified, with most of them causing the rarer, inherited form of the disease.

A new addition to a list of genes that are related to development of ALS, the most common form of MND, has been discovered by researchers from King’s College London. Dr Bradley Smith and colleagues screened genetic data of an unusually high number of people of European origin: 751 with inherited – familial – ALS (fALS) and 180 with non-inherited – sporadic – ALS (sALS). Detailed analysis of this data found that specific mutations in the ANXA11 gene are associated with around 1% of all fALS and 1.7% of all sALS cases.

While this may seem like a small percentage, it is another great finding that can tell us more about the mechanisms of MND. Discovery of new genes is a very important first step that can take us closer to understanding how and why a gene causes motor neurones to die. Here is what Dr Brad Smith found out so far about why mutations in ANXA11 are toxic to motor neurones.

What is ANXA11 and what does it do?

ANXA11 is a gene that encodes information for a protein called annexin A11. Its normal function is not known but it does link with internal walls of cell compartments called membranes when it is switched on by binding calcium. ANXA11 appears to form vesicles (small fluid-filled sacks) that move within cells, therefore ANXA11 may be involved with transport and the delivery of cargoes within and between motor neurones. One way mutations in the ANXA11 gene are likely to cause death of motor neurones is via a protein called calcyclin. This protein that binds with calcium molecules is important for maintaining the internal structure of annexin A11.

According to the current research paper, ANXA11 mutations lead to a reduced ability of calcyclin to bind and may result in accumulation of annexin A11 in motor neurones as a consequence, ultimately causing their death.

To make it a little bit easier to understand, we can picture the internal structure of annexin A11 as scaffolding. As long as all the screws fit and work well, the scaffolding is static and allows workers to move up and down freely and safely. However, if a large number of the screws would disappear (ie there would be no binding in between the poles), the whole structure would collapse. If this was to only happen at one building site, it might not cause a big disruption.

However, if bolts went suddenly missing from all scaffoldings across a town, the poles would hoard up on the streets, making it impossible for the town and its residents to function. In a similar way, when internal structures of the annexin A11 proteins crumble due to inability to bind (which is where calcyclin is important), they accumulate and cause a big disruption to the cell.

What needs to be investigated next?

Now that the researchers know another gene that is implicated in developing ALS, they want to look at the process of how this causes death of motor neurones in more detail. Specifically, they will investigate how exactly the role of vesicular transport and calcyclin binding is affected. The researchers will use tissue from people who donated their brain and spinal cord for research and they will also model the function of calcyclin and ANXA11 in neuronal cells and using zebrafish models of MND. This follow-up research project  will be funded by the MND Association as a PhD studentship and is due to commence in October 2017 (our ref: 888-792).

“This study shines the spotlight on a new family of proteins for further investigation in their role in ALS biology. ANXA11 is yet another rare gene on the ever growing ALS list, but it emphasises the need for large gene sequencing consortiums to provide the power to detect the remaining genetic culprits. The concert of this rapidly expanding list of smaller ALS genes could be critical in nailing key mechanisms in the disease process that have so far been elusive.” Dr Brad Smith

Original research paper: Smith, Bradley N. et al. (2017). Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis. Science Translational Medicine, 9(388). doi: 10.1126/scitranslmed.aad9157