Profilin 1 identified as a cause of inherited MND

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An MND causing gene called profilin 1 has been identified as the cause of about two percent of cases of inherited MND. This finding provides new insights into the causes of MND and suggests a potential role of the cellular scaffolding in MND. The finding was published in the 15 July edition of the prestigious journal Nature. This international collaborative study was led by Dr John Landers, at the University of Massachusetts Medical School, USA.

Using cutting-edge genetic technology, Dr Landers and colleagues first identified genetic mistakes in the profilin 1 gene in two families with inherited MND. To verify these findings, they went on to identify five additional families that also have mistakes in the profilin 1 gene. They did this by examining the genetic spelling of this gene in 272 further people with inherited MND (with no known genetic cause). This means that the genetic mistake could account for approximately two percent of cases of inherited MND.

Four different genetic mistakes were identified in the profilin 1 gene in the seven identified MND families. Three of these genetic mistakes were not found in any healthy controls, which mean that these mistakes are most likely a direct cause of MND. The forth genetic mistake was identified in a small number of healthy control samples, which could mean that this mistake could be a less significant cause of MND.

What does profilin do?

Profilin plays a vital role in maintaining and shaping the cells scaffolding – the cytoskeleton.

The cytoskeleton can be thought of as being made up of stacks of Lego bricks, called filaments. To maintain the shape of the cell, these bricks push against the cell membrane. To stretch and move the cell, more bricks (called actin) are added to the outermost end of the filament, which forces the membrane to extend. Toward the innermost end of the filament, the actin units separate, similar to pulling off individual bricks from the bottom of a stack, where they’re then collected and attached to profilin. Profilin then recharges and recycles the actin units, so that they’re ready to be added to the top of the filament again.

What did the research group find?

Through this study, the research group identified that the ability of profilin to attach to actin is affected by the genetic mistakes, making it ‘clumsy’. They also identified that the mistakes affect the ability of the cells to grow, which could be an attributing factor to how these mistakes can cause MND.

In this study, the researchers also confirmed that profilin is normally found throughout the ‘factory floor’ of the cell, the cytoplasm. However, when profilin is faulty the research group identified that it often assembles into clumps of protein marked for destruction – a hallmark of MND.

Interestingly, they also identified that when profilin is faulty, TDP-43 also clumps together. This suggests that faulty profilin may also cause MND through its effect on TDP-43. It’s also worth noting that when TDP-43 is faulty, profilin is not found within the clumps of faulty TDP-43 suggesting that profilin has an effect on TDP-43 and not vice-versa.

What does this mean for people with MND?

Profilin 1 is the twelfth MND causing gene to be identified in MND, which means that we are one step closer to knowing all of the genetic causes of MND. Learning more about how genetic mistakes can cause the rare inherited form of MND (5-10% of cases)  helps us to learn more about all forms of MND as the more common sporadic form is clinically indistinguishable to the inherited form.

As this genetic mistake is thought to only be attributed to a small number of families with MND, it is currently unknown if a genetic test will be developed for inherited MND. If you have inherited MND and want to find out more information about genetic testing, please speak with your doctor or neurologist.

What does this mean for the future of MND research?

These findings will need to be verified in larger numbers in different populations to determine a more accurate figure for how many families are affected by mistakes in the profilin 1 gene. More work will also need to be done to determine how the cytoskeleton is affected in MND and whether it can provide any therapeutic targets to treat MND in the future.

In summary, problems with the cytoskeleton have long been thought to be involved with MND, but having a direct genetic cause of MND strongly associated with the cytoskeleton will most likely reignite this avenue of research in the coming years.

Wu C-H et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 2012 doi:10.1038/nature11280

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