Copying, transporting and creating proteins – what could possibly go wrong?

Proteins are the building blocks of our cells and have a variety of important roles within our bodies. The instructions for how to build our proteins sit within our DNA, our genetic code in the control centre of our cells (the nucleus). There are many steps to go through from reading that ‘raw’ instruction to ending up with a fully functioning protein.
However, the amount of information held within our genetic code is so huge that only small segments of it are read and transferred to the factory floor, as and when they are needed. These copies, known as messenger RNA, are small enough to be transported to the ‘factory floor’ of the cell to large machine-like entities called ribosomes where the copy is read, and used to create the resulting protein.
When I was doing my A levels and later at University (yes, that long ago!), we were taught that only 1% of the genetic code ever made it to the factory floor. This held true until a couple of years ago. However, as explained by Professor Bob Brown in his presentation at the ‘RNA and protein processing’ session this afternoon, such is the change in our knowledge in that area, we now know that 95% of our genetic code makes it through to the first step of making proteins.
This was a key piece of context in trying to understand the role that TDP43 plays in functioning cells – never mind specifically in motor neurones or in cases of the presence of damaged TDP43 in MND!
Professor Brown, University of Massachusetts Medical School, Boston, USA went on to give an enlightening review of what has been uncovered about this fascinating protein (TDP43) so far. Once the protein of TDP43 has been correctly made, its function is to go back and ensure that other proteins are correctly made too – the so called ‘reading helpers’ of the cells, or ‘editors of instructions’. Another new fact to me from this talk was that TDP43 is involved in editing or reading up to ONE THIRD of all proteins within the cell. That’s a city fat cat type of job! So how is it all related to it’s function in MND?
Some elegant experiments have shown that TDP43 regulates how many copies of it’s own protein are made. However, the regulation takes place in the control centre of the cell (see the top of this blog). If TDP43 gets stuck or waylaid on the factory floor, it can’t get back to press the stop button in time. So it’s thought that more and more protein is made, accumulating on the factory floor until that accumulation can be seen as the protein deposits so characteristic of what you see of motor neurones affected by MND down the microscope.
Part of the editing work that TDP43 does so well is known as ‘splicing’. In true ‘Blue Peter’ style, here is a description of that process that Kelly prepared before I flew out to Sydney:

Alternative protein
One gene can hold the instructions for a number of different versions or variants of a protein. These variants are created when different parts of the gene are used in alternative combinations. This is a normal process and it’s called ‘alternative splicing’. This complicates matters in terms of genetic research, as even though we have approximately 20,000 genes, we could potentially have a much higher number of functional proteins because of alternative spliced variants.

How does alternative splicing work?
The picture (below) depicts a simple version of how a gene can be alternatively spliced, given three ‘parts’. The example demonstrates that the first version of the protein is made up of parts 1, 2 and 3, whereas version two is made up of only parts 1 and 3. These resulting proteins would go on to function in our bodies in potentially different ways. It is therefore possible for a number of different proteins to be created given one set of original instructions in the genetic code.



Read our official day one symposium press release on our website.

The importance of FUS

It is really quiet in the office today, with a few colleagues out and about for various reasons. As soon as the thought entered my head about having a productive day with no distractions, an email landed in my In Box. Had I seen the research report mentioned in this press release? A quick scan of the release and my thoughts were ‘no’ (I haven’t seen it), ‘how exciting’ and ‘well there goes my quiet afternoon’ in quick succession!

The bottom line of the research is that some MND researchers in Chicago, USA led by Dr Han-Xiang Deng and Professor Teepu Siddique have been able to make a connection between a biochemical pathway recently implicated in the rare, inherited form of MND (known as familial MND) and sporadic MND. They have found clumps of the ‘FUS’ protein in motor neurones of people with familial MND AND in motor neurones of people with sporadic MND too.

One of the keys to understanding what causes motor neurones to die in MND is to understand which proteins are deposited in affected motor neurones. Deposits, or clumps, of proteins are common to many neurodegenerative diseases, the main difference between the diseases is which proteins are found. A protein called TDP-43 was the first protein discovered to be consistently deposited in the motor neurones of people who had MND. The results from this Chicago research group showing that FUS protein accumulates in most cases of people with MND is the second discovery of its kind.

The efforts of many people around the world will now be focussed on confirming these exciting results which take us closer to understanding the causes of MND.

All of these studies have been conducted using the post-mortem brain and spinal cord tissue of those that have donate these tissues for research after their deaths. A big thank you to anyone who has helped this happen for close family and friends. More information on this generous opportunity to help MND research can be found on our website.