This week a new article was published in Nature, one of the best journals in the scientific field. It is a review entitled “Decoding ALS: from genes to mechanism” and is an excellent summary of what we know and what we think might cause MND. The article contains some great figures, in particular figure 2 (see below) which summarizes the possible disease-associated processes/mechanisms that contribute to MND.

While there is a lot going on in this figure, over the next few blogs I will try and breakdown each of these processes and go into detail about how each process is involved and what research is being done to combat the disease in this area.


a. Disturbances in protein quality control

Protein homeostasis is a term used to describe how the cell maintains the balance between the production and removal of proteins. How are proteins made? They are made from DNA and RNA. Most people are familiar with DNA, but not RNA and RNA plays an important role in MND. If we think of proteins like a piece of flat-pack IKEA furniture, then DNA is the blueprint and RNA is the instructions that come in the box with your furniture pieces. DNA is made up or two strands that are held tightly together. In order to make proteins, cells will separate these strands of DNA and make a complimentary copy of one strand –  this is called RNA. Like the blueprints for a table and a bookshelf are very different, the DNA and RNA sequences are very specific for each different protein.

Now most people (or is it just me?) when they are putting together IKEA furniture will end up with a panel on back-to-front or a door on upside-down! The panel can be easily removed, switched around and put on the right way. This can happen with proteins as well. The cell can make mistakes when building the proteins and the protein can end up a funny shape. This is called protein-misfolding. The cell can pull apart the protein and re-build it into the correct structure or if there are too many faults with it, it gets stamped with a special protein called ubiquitin (Ub) which tells the cell that the protein is to be broken down via the cell’s waste removal system. All of this happens in a big warehouse within the cell called the endoplasmic reticulum or ER.



When a gene contains a mutation, like in the MND gene SOD1, the blueprint and hence the instructions are incorrect, so the protein it produces is often misfolded. This means the protein quality control system starts working in overdrive, disassembling and re-building proteins and sending faulty proteins to be degraded. The overload on this system is termed ER-stress (you can imagine the warehouse becomes very overworked!).

Dysfunction in the two waste removal pathways, the proteasome-system and autophagy pathway, have also been reported in MND. Scientists have reported a build-up of some and a loss of other key proteins that are involved in these two pathways. In addition mutations in genes that are directly involved in these pathways (including Optineurin, Ubiquilin 2, Sequestosome 1, valosin-containing protein and CHMP2B if you want to read more) are also known to cause MND.

In MND the ratio between protein production, assembly and breakdown becomes unbalanced and misfolded proteins, tagged with Ub, begin to build up within motor neurons. These structures are called Ub-aggregates or Ub-inclusions and can be seen in neurons grown in the lab, and in the brain and spinal cords of MND mice and MND patients.


Protein aggregates and inclusions are hallmarks of MND and are also found in a number of other neurological diseases. The presence of these aggregates and the mutations in genes from the waste removal pathways point to this area as a key disease causing process. This makes it an ideal target for therapies!

Therapies targeted at restoring protein homeostasis

Scientists are investigating restoring protein homeostasis in a number of ways. Drugs that act on the ER (the warehouse) to reduce ER stress have shown promise in mouse and worm models of MND.  Also drugs that improve the waste removal systems, autophagy and the proteasome-system, are also being trialled in cell and animal models of MND and one compound is currently in Phase II clinical trial in MND patients in the United States. In addition, therapies that directly target the misfolded protein are being developed and investigated. Probably the most advanced therapy of this type is aimed at taking down mutant SOD1, the first discovered MND gene, by creating small molecules that specifically recognise and shut down misfolded SOD1. While a lot is being done in this area in MND research, it is important to remember that these pathways are important for the maintenance of all proteins in the cell, not just the ones that misbehave in MND. Therefore, researchers much be careful not to tip the balance of protein production and removal too far.

If you would like to learn more about these potential therapies, here are a few review papers:

  1. Cipolat Mis, M. S., et al. (2016). “Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets.” Mol Cell Neurosci 72: 84-90. Click here for reference
  2. Yerbury, J. J., et al. (2016). “Walking the tightrope: proteostasis and neurodegenerative disease.” J Neurochem 137(4): 489-505. Click here for reference
  3. van Zundert, B. and R. H. Brown Jr (2016) “Silencing strategies for therapy of SOD1-mediated ALS.” Neuroscience Letters. Click here for reference