A collaborative American research group, led by Prof Aaron Gitler from Stanford University School of Medicine in California, has identified a potential therapeutic target for MND using yeast.

The toxic activity of the MND-linked protein TDP-43 was suppressed when a gene called DBR1 was deleted from yeast and mammal cells.

The study marks the first steps in the identification of a treatment that can target TDP-43, which is found to clump together in over 90% of cases of MND.

The study was published in the prestigious journal Nature Genetics.

Toxic tangle of TDP-43

To develop effective treatments for MND, we need to find ways of targeting the systems that go wrong to cause the disease.

One hallmark of MND is the accumulation of tangled lumps of protein – including TDP-43.

For years, researchers didn’t know whether the clumps of TDP-43 they could see was a by-product of MND, or a cause of the disease. That was of course, until researchers identified that mistakes in the TDP-43 gene can cause inherited MND in 2008. Since then, researchers have been busy creating new disease models to learn more about how TDP-43 can cause MND.

So far, at least 400 studies have been published to better understand TDP-43 in MND (search terms ALS, FTD, variations of TDP-43 on Pubmed).

Yet we still don’t know whether TDP-43 is doing harm by being over active or under active. We do however know that it’s found in the ‘factory floor’ of the cell, called the cytoplasm, when it’s normally found in the control centre. Using this information, it’s possible to focus on therapies that decrease the toxic effect of TDP-43 rather than to increase or decrease the amount of TDP-43.

This is exactly what a collaborative American research group, led by Prof Aaron Gitler has done.

Using yeast, Prof Gitler and colleagues performed two unbiased genetic screens in different laboratories using different techniques. By doing this, they verified a list of genes that can modify the effects of TDP-43 when deleted – by either enhancing the toxic effect or suppressing it.

Out of the list of resulting modifiers, the research group chose to investigate a suppressor of TDP-43 toxicity, a gene called DBR1.

DBR1

Far from a classic Aston Martin sports racing car (also named DBR1), DBR1 in biological terms is an ‘RNA lariat de-branching enzyme’. It plays an important role in recycling genetic ‘junk’.

Our genes are split into segments within our genetic code, separated by what’s often referred to as ‘junk’ DNA. These sections of junk, known as introns, don’t code for anything, but often perform other important roles.

When a gene is copied into its intermediate form of RNA (before these instructions are used to create a functional protein), it needs to be edited to remove the introns, leaving the vital instructions intact. This involves the introns forming loops of RNA – called lariats – which cut away from the rest of the copy. This leaves only the instructions for the gene product. These lariats then move away from the control centre of the cell (the nucleus) to be recycled.

DBR1’s role normally cuts these lariats open into strings, which can then be recycled. When in a lariat form, RNA is resilient to being recycled. DBR1 therefore plays an important role in recycling intronic RNA in the cell.

What happens when DBR1 is deleted?

When the research group deleted DBR1, intronic lariats accumulated in the factory floor of the cell (the cytoplasm). These lariats then competed to bind to TDP-43, acting as a decoy. This stopped TDP-43 from performing its dastardly deeds when faulty – chopping up essential RNAs within the cell –which could be contributing to the cause of MND.

By deleting DBR1 in yeast and in rat neurones grown in a dish, the research group identified that it increased the chance of neurone survival by nearly 20%.

This means that identifying a therapy that can decrease the amount of DBR1 could be a potential treatment for MND.

Reliability

Prof Gitler and colleagues independently verified their results from the genetic screen in yeast using different laboratories and different methods.

This is significant in terms of its reliability, as this often has huge repercussions for future research.

This topic was recently discussed in the popular science magazine New Scientist in an article called ‘Is medical science built on shaky foundations?’ In the article, the writer explains that a number of pharmaceutical companies have recently announced their failure to replicate a large number of promising results of potential drug targets from published studies.

It’s vital that if we are to identify a treatment for MND that works, that the evidence that led it to be tested in humans is solid. Gaining evidence to suggest the effectiveness of a treatment means replicating the results using independent researchers and using different methods to put an idea through its paces. This ensures that the original results aren’t identified as a coincidence and can be relied upon.

The decision by Prof Aaron Gitler’s group to reproduce their genetic screen independently, using different methods should be applauded. It means their findings are unlikely to be added to the heap of potential targets that cannot be reproduced in other studies.

Being thorough to identify potential targets may take more time, but it’s likely to produce more fruitful results in the long haul.

Looking forward

There are many steps left to climb with the development of a treatment that targets TDP-43. For example, the research group will need to determine whether stopping DBR1 could itself be toxic due to side effects. They also need to determine where the ‘therapeutic window’ is with this therapy – where it’s both effective and safe.

This study also identified many other modifying factors for TDP-43, which can begin to be investigated by other research groups for their potential as a therapy for MND.

As this is the beginning of the story of TDP-43 specific treatments for MND, it will inevitably be a long journey to answer these questions and to bring treatments to the doctor’s prescription pad.

Hopefully, the beacon of rigor and scientific righteousness that this study symbolises will continue and we will see the first TDP-43 therapy being developed for MND in the coming years.

References:

Maria Armakola et al Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models. Nature Genetics 2012; doi:10.1038/ng.2434

http://www.newscientist.com/article/mg21528826.000-is-medical-science-built-on-shaky-foundations.html