Due to the collaboration, hard work and partnerships with people affected by motor neurone disease (MND) who generously take part in research, new pieces of the complex MND puzzle continue to be found. These pieces can come in many forms and one such type of discovery is of the genes that cause MND – in this case, the identification of the ‘CYLD‘ gene. Each time a genetic cause is identified, researchers can look at what the identified gene does in the body, and how it is involved or interacts with different biological processes. By understanding this, it is then possible to begin to develop treatments that target these processes.
Identifying causative genes is incredibly difficult, like finding a small needle in a very large haystack. Researchers across the world have identified some of the most common genetic causes of MND and FTD (e.g. C9orf72) but many of the rarer causes or risk factors are still undiscovered. However, by sheer hard work and brilliance with computational analysis of huge amounts of data, it is possible – but only if samples are available through generous partnerships from people with MND.
By super detective techniques involving the latest cutting-edge gene sequencing, bioinformatics and computation analyses, it is possible to identify single ‘spelling mistakes’ in family members with the disease. Together this is known as ‘linkage analysis’.
One such example of the identification of a genetic cause has been published recently in the journal, Brain, by researchers in Australia, in combination with strong teamwork and collaboration from researchers and patient collections around the world, including MND Association supported MND researchers.
Dr Carol Dobson-Stone and Associate Professor John Kwok of the University of Sydney originally performed this study in an Australian family with a history of frontotemporal dementia (FTD) and MND that spanned four generations but had no mutation in known disease-related genes. They found that a single genetic ‘spelling mistake’ (mutation) in a gene called ‘CYLD’ was present in people with disease but it didn’t appear in unaffected family members. This gene mutation can cause both ALS and FTD (as is the case in C9orf72 repeat expansion, the most common genetic cause of MND).
This project utilised the data and samples from many different cohorts of patients with MND and/or FTD as well as controls, including the samples obtained from the MND Association’s own UK MND Collections (formerly known as DNA bank, read more on our previous blog post here). The samples for the MND Collections were collected between 2003 and 2012 via a project that was jointly funded by the MND Association and the Wellcome Trust.
By analysing all the information available from the many different cohorts of samples and data, the researchers were able to confirm that spelling mistakes in CYLD were present in some cases, but their prevalence was low. Although mutations in the CYLD gene are likely to be very rare, the gene was found to interact with at least three known FTD/MND proteins.
Mutations in these three known genes result in a loss of an important process called autophagy – the cells’ waste disposal system that acts to clean out damaged cells to regenerate newer, healthier cells. The researchers here found that the genetic change in CYLD can also slow down autophagy function, allowing waste to accumulate inside motor neurones leading to a build-up of clumps of protein that are toxic to cells. This suggests that CYLD may play a central role in the development of these disorders.
Dr Carol Dobson-Stone, lead author of the published paper, has written a summary of the work for us at the MND Association and is presented below:
“We have identified a new disease gene that can cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). FTD is a dementia disorder similar to Alzheimer’s disease but affects a different region of the brain. This leads to progressive disease characterised by severe behavioural and/or loss of language abilities. ALS is the most common type of motor neuron disease. It leads to impairment of voluntary muscle movement and progressive paralysis. Both diseases are invariably fatal, and we lack effective treatments for them.
“Working with a large, multigenerational family with members affected with FTD and/or ALS, we have pinpointed the causative gene. The culprit is CYLD, a gene encoding an enzyme that has been previously implicated in skin tumour disorders. Interestingly, the mutation we have identified in this family has the opposite effect to the skin tumour disorder mutations: the tumour mutations lead to a reduction in enzyme activity, whereas the FTD-ALS mutation leads to an increase in enzyme activity.
“From what we know so far, the frequency of mutations in this gene in people with FTD and/or ALS is very low. However, the importance of this discovery is that it highlights a critical biological process that leads to the death of brain and/or nerve cells in these disorders. By understanding more about these processes, we should be able to design drugs to target them in order to treat FTD and ALS. So, the discovery of this gene hopefully brings us one step closer to identifying a treatment for these disorders.
“We are now focussed on identifying protein partners that work with the CYLD protein. Some of these are encoded by other disease genes known to cause FTD and ALS, including OPTN, TBK1 and SQSTM1. This suggests that CYLD may play a central role in the development of these disorders. We are also developing mouse and cell models of the CYLD mutation, in order to understand what biological pathways are affected when this gene is mutated, and as a tool for testing new drug treatments for FTD and ALS.”
We thank Dr Carol Dobson-Stone for this addition to our research blog and look forward to hearing of updates.
Carol Dobson-Stone, Marianne Hallupp, Hamideh Shahheydari, et al. (2020). CYLD is a causative gene for frontotemporal dementia – amyotrophic lateral sclerosis. Brain, 143(3). https://doi.org/10.1093/brain/awaa039