The TBK1 jigsaw puzzle

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Following on from the identification of the gene TBK1 as a contributory risk factor for MND in February, the plot thickens further with research published yesterday by Dr Jochen Weishaupt and colleagues.

Published in Nature Neuroscience, the team found mutations in the TBK1 gene as a cause of both inherited MND and frontotemporal dementia in Germany and Sweden.

Screening DNA for clues

The majority of cases of MND are caused by a combination of subtle genetic, environmental and lifestyle factors. However, in 5-10% of cases there is a family history of the disease where the genetic factor plays more of a pivotal role. This is known as inherited MND.

Initially unveiled during the 25th International Symposium on ALS/MND in December 2014, Dr Weishaupt from Ulm University in Germany identified that mutations in the gene TBK1 were found in those with a family history of MND and frontotemporal dementia. This research, links to research published in February 2015, which identified variations in TBK1 as a contributory genetic risk factor in a small number of cases with no family history.

By screening 252 inherited MND DNA samples, with no known genetic cause, the researchers identified mutations in TBK1 as a cause of these two diseases in Germany and Sweden. This equates to TBK1 causing 1.5-2% of total inherited MND cases in this population.

Recycling breakdown

TBK1 is part of the cell’s recycling system known as ‘autophagy’. Previous research has shown that this breaks down in MND, and in February 2015 researchers linked TBK1 to the other MND genes involved in this process, p62/SQSMT and OPT (find out more). Dr Weishaupt and colleagues have also identified TBK1 and confirmed that this is a major process that breaks down in inherited MND.

Zebrafish confirmation

Dr Weishaupt and colleagues identified that the developing motor neurones were much shorter in zebrafish with the mutated TBK1 gene. The work in the zebrafish was conducted to find out whether the TBK1 gene mutation has a direct impact on the motor neurones themselves. They found that the developing motor neurones were unable to branch and connect to other cells correctly, confirming that TBK1 does affect the motor neurones of the fish.

Zebrafish are ideal models for helping scientists understand what happens in MND. Unlike mice and fly models, zebrafish have transparent embryos which enable scientists to get a unique view of the developing neurones under a microscope.

Solving the TBK1 puzzle

Dr Brian Dickie, our Director of Research Development, commented on the research “Dr Weishaupt and colleagues have identified TBK1 as a cause of inherited MND and frontotemporal dementia in Germany and Sweden.

“The next step would be to find out whether this gene mutation is present in other populations, like the UK-as we know that this is not always the case – and to develop models to study TBK1 in detail.

“TBK1 has further strengthened the link between frontotemporal dementia and MND. We know that inherited MND and the more common ‘sporadic’ form are identical in their presentation and disease progression in the clinic. The TBK1 gene overlap, and the breakdown of autophagy in the cell, now shows a similarity at a cellular level, which MND researchers can go on to further understand and develop potential treatments that target this common process.”

What does this mean to me?

This research by Dr Weishaupt and colleagues has identified the TBK1 gene as a cause of inherited MND in 1.5 – 2% of inherited MND cases in Germany and Sweden. The next step will be to find out whether the TBK1 gene mutation is also found in other countries, like the UK.

Because, this is a new inherited MND gene, confirmation studies are needed before a genetic test can be developed. The overlap between those with a family history and apparently ‘sporadic’ MND cases means that TBK1 will need to be investigated further, as this will affect the interpretation of any genetic test result.

As with previous inherited MND gene discoveries, we are likely to see more research into identifying and understanding TBK1 over the coming year. The 26th International Symposium on ALS/MND abstract submissions are now open (find out more about abstracts here), and it will be interesting to find out how many TBK1 abstracts are discussed in Orlando this December.


Freischmidt et al (2015) Nature Neuroscience

Please note that this research was initially presented by Dr Jochen Weishaupt on the 7 December 2014 during the late-breaking news session of the 25th International Symposium on ALS/MND and will also be presented during the European Network for a Cure of ALS (ENCALS) meeting in May 2015.