Unravelling TDP43 toxicity

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Background to TDP43

A characteristic sign of motor neurones affected by motor neurone disease is the clumps of protein visible down a microscope. Although these proteins have been observed in motor neurones from people affected by MND since the earliest descriptions in the 1870s, a key discovery was made when the identity of a protein, common to all types of MND, was unveiled as ‘TDP43’ in 2008.

Two years later a second protein called FUS was also been found to be common to all types of MND. More information on this aspect of MND can be found in an article on our research blog.

One of the exciting things about these two discoveries was that they were both linked to a set of biological pathways, known as RNA processing. The was the first major clue that RNA processing was involved in MND. When the discovery of genetic defect in the C9orf72 gene came along in 2011, that made a third MND-causing gene defect that linked to RNA processing.

The first session of the 24th International Symposium on ALS/MND after lunch yesterday was dedicated to the topic of RNA processing and dysregulation. Several of the talks presented work on understanding the role of TDP43 in MND.

So what is RNA processing?

RNA processing is about ensuring the correct version of a protein is made at the ‘right’ time – the time that the cell needs it.

At school I was taught that DNA contains the gene, or the instruction to make a protein. Next, RNA takes a copy of the DNA (the instructions) and the protein is made from the RNA copy. In the last 10 years or so we know a great deal more about how RNA works and its role in making proteins has been uncovered. Find out more about genes and proteins here.

One thing that is now known is that in order to make working copies of most proteins, other, already-made proteins help the RNA with its job. These are known as RNA binding proteins. TDP43 acts as an RNA binding protein.

So to understand how TDP43 causes motor neurons to die in MND, we need to know which proteins it helps to make from RNA – which proteins it interacts with.

How can we study TDP43?

Yesterday we heard about two areas of MND research looking at different aspects of studying TDP43. One from Professor Zarnescu based at the University of Arizona was looking at a fly model of mutant TDP43 to study how to reduce its toxicity. In the second study we heard from MND Association clinical fellow, Dr Pietro Fratta about the creation of a physiologically relevant mouse model of MND.

Dr Zarnescu designed a series of experiments in a fly to test her ideas that TDP43 is toxic by causing other RNA binding proteins to ‘abandon’ (my words!) their normal roles in helping to make proteins. They do this by sticking or binding to TDP43.

The researchers identified that an RNA binding protein called ‘fragile X Mental Retardation protein’ or ‘FMRP’, interacts with TDP43. When there is less FMRP TDP43 is more toxic and conversely, when there is more of it, TDP43 toxicity is reduced.

Perhaps another way of thinking about it is that TDP43 and FMRP play truant together. In the absence of FMRP, TDP43 gets up to more mischief and when there is more FMRP, the damage of TDP43 is reduced!

Models of TDP43 – let me count the ways (to do it)

Fly models can teach us a lot about understanding MND, however a model closer to humans is to look at mice.

Traditionally, mice models of MND are created by introducing a copy of the damaged human gene into the mice. Most ways of doing this introduce perhaps 20 extra copies of the gene. So, it isn’t clear whether the damage seen is due to the fact that there are so many copies around, rather than the damaged gene itself.

One way to get round this is to use a new technology called ‘BAC transgenics’. The MND Association are funding the development of a number of new models of this kind, introducing only one copy of the damaged gene. This work is being conducted in Professor Kevin Talbot’s lab at the University of Oxford.

Dr Pietro Fratta
Dr Pietro Fratta

Dr Pietro Fratta, based at UCL in London, introduced another way of developing a physiologically relevant mouse model of TDP43 toxicity – by looking for defects in the mouse version of the TDP43 gene. Working with colleagues at a Medical Research Council unity in Oxford, Dr Fratta found two mice. Both had a defect in TDP43, but in different areas of the gene.

Generally damage to genes has one of two effects, the damage either prevents the normal function of the gene – known as a loss of function. Or the damage somehow creates another toxic job for the gene to do, known as a gain of function.

At the Symposium Dr Fratta presented a series of elegant experiments showing just how different the effects are if you have damaged areas of the gene. One has a gain of function effect and the other has a loss of function effect.

So what?

Both Dr Zarnescu and Dr Fratta’s research studies reminded me just how complex TDP43 is. But also how important it is to get to the bottom of how TDP43 works, so we can develop therapies for moderating its effects. Going back to my earlier analogy, we need to get it to stop playing truant!

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