Dobson-Stone et al (2020), “CYLD is a causative gene for frontotemporal dementia – amyotrophic lateral sclerosis” Brain 143:783-799

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. It’s the second most common cause of younger-onset (before age 65) dementia, after Alzheimer’s disease. ALS is the most common type of motor neuron disease, brought into the public eye by the 'Ice Bucket Challenge'. 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.

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