TUBA4A – New inherited MND-causing gene identified

24 October 2014

An international team of ENCALS researchers, led by researchers based at King’s College London, have identified mistakes in the TUBA4A gene as a new cause of the rare inherited form of MND.

This new MND-causing gene causes the cell’s structure, or skeleton, to break down – resulting in the cell being unable to transport molecules from one end of the cell to the other.

TUBA4A falls off the track

The TUBA4A gene is responsible for the Tubulin, alpha 4A protein and the researchers have found that the genetic mistake in the TUBA4A gene causes the microtubule network to breakdown in MND.

The microtubule network is a bit like a railway system. Normally, the healthy TUBA4A protein acts like a train, allowing the cell to transport molecules along this railway track to where they’re needed. As well as transporting molecules around the cell, the microtubule also acts as a skeleton within it (known as the ‘cytoskeleton’).

The faulty TUBA4A protein (the train) created by the genetic mistake in the TUBA4A gene is unable to join the microtubule railway track in this form of MND. This means that all the ‘passenger’ molecules that need to move from one end of the cell to the other are stuck and unable to ‘board’ their specific TUBA4A train.

This disruption affects the whole railway system, causing the microtubule railway track to become unstable, breaking down the cell’s shape and structure in the process.

Inherited MND – the story so far

In the majority of cases, MND is thought to be caused by a combination of genetic, lifestyle and environmental factors.

However, we know that 5-10% of cases of MND are characterised by a family history of MND and the related neurodegenerative disease frontotemporal dementia (FTD). In these cases, sometimes known as inherited MND, the genetic factor plays more of a pivotal role.

In 1993 researchers discovered the SOD1 gene as a cause of inherited MND. It was not until the late 2000s more inherited MND genes were identified, due to advances in genetics and gene-hunting technologies. To date approximately 60% of the causes of inherited MND are known, however researchers are still hunting for the remaining unknown genes.

TUBA4A is the second inherited MND gene to be identified in 2014, following on from the discovery of the Matrin 3 gene in April 2014.

Identifying TUBA4A

The researchers identified TUBA4A by looking for rare genetic changes in 363 inherited MND cases from six countries (including samples from the UK MND DNA Bank). They also checked that TUBA4A was specific for MND by comparing this with over 13,000 healthy controls.

MND Association-funded researcher, Dr Bradley Smith, based in Professor Chris Shaw’s lab at King’s College London said: “By sequencing the DNA of hundreds of unrelated MND patients with a family history and comparing it to 1000s of controls, (people who don’t have MND), we identified a significant enrichment of mutations (mistakes in the DNA code) in the gene TUBA4A.

“This gene is essential for forming the physical architecture of a neuron, like the internal frame of a building that holds everything together. This framework has a dual function and also acts as railroad tracks that transport cargoes back and forth along the neuron. With experiments we proved that mutations destabilize the neuronal structure and stop the building blocks of the framework coming together.”

What does this mean for people with MND?

By identifying another inherited MND-causing gene, researchers are furthering our understanding of the causes of MND. TUBA4A has emphasised the importance of the cytoskeleton and its’ involvement in some cases of MND.

Dr Smith said: “The percentage of cases with TUBA4a mutations is modest, but is important to the field and exciting as it adds to a rapidly growing list of MND genes that have the same outcome!”

Head of Research at the MND Association, Dr Belinda Cupid, commented on this research: “Thanks to the UK MND DNA bank, this research has been able to identify the TUBA4A gene as a new cause of inherited MND – furthering our understanding of the cause of the disease and the role of the cytoskeleton.

Smith BN, Ticozzi N et al Neuron Volume 84 Issue 2, p324–331, 22 October 2014: http://dx.doi.org/10.1016/j.neuron.2014.09.027

Source: http://mndresearch.wordpress.com/2014/10/22/new-inherited-mnd-causing-gene-identified-tuba4a/