Scientists discover mechanism behind motor neuron disease

Scientists say they have made a breakthrough in understanding the cause of both motor neurone disease and a rare form of dementia.

They have discovered that a protein called FUS causes brain cells to die in both conditions.

The researchers, from Cambridge and Toronto, said they were cautiously optimistic their findings could one day to lead to improved treatments.

The study is published in the journal Cell.

Motor neurone disease (MND), also known as ALS, is a progressive and terminal disease that damages the function of nerves and muscles, resulting in severe damage to the brain and spinal cord.

It affects up to 5,000 adults in the UK at any one time.

Frontotemporal dementia is a form of dementia that causes changes in personality and behaviour, and language difficulties.

Both conditions are caused by the death of brain cells and this study shows that a similar mechanism is involved in each…

The researchers looked at a protein called FUS which is vital for nerve cells to work properly.

It is able to change state between oily droplets and more solid jellies and in both diseases it can become trapped in its jellied form.

Synapses - the point where two nerve cells meet - are highly active and need to produce a lot of new proteins in order for messages to be passed from one cell to the next.

FUS grabs the instructions for those proteins as it becomes a jelly and releases them as it becomes an oil.

Prof Peter St George-Hyslop, from the University of Cambridge, told the BBC: "In the jelly phase it is like a fruit salad - jelly with bits of fruit - that move around the cell and the bits of fruit are the machinery needed to make proteins."

But if FUS stays jellied then that machinery is not released and the brain cell fails to function and eventually dies.

In motor neurone disease, the FUS protein can be mutated and more prone to becoming stuck in a jellied form.

In frontotemporal dementia, the problem is with other enzymes which help FUS change state, and they tip the balance towards the jelly.

Prof St George-Hyslop says these enzymes could be the key to treating both conditions.

"What we didn't know is really how this process is governed and that's the crucial piece of information," he said.

"So can we use these enzymes that control the process to inhibit or accelerate it - that's the big step forward."

The FUS protein is involved in a delicately balanced system and finding a treatment for MND and dementia will not be easy.

For example, a drug that made FUS too oily would cause as many problems as when it becomes too jellied.

The latest discovery was made using human cells that resembled neurons as well as neurons from frogs.

The scientists hope future research will discover drugs that can help FUS revert to its oily state.

"It now opens up a new avenue of work to use this knowledge to identify ways to prevent the abnormal gelling of FUS in motor neurone disease and dementia," added Prof St George-Hyslop.

http://www.bbc.com/news/health-43838545

https://www.doximity.com/doc_news/v2/entries/12058502

Qamar S, Wang G, Randle SJ, Ruggeri FS, Varela JA, Lin JQ, Phillips EC, Miyashita A, Williams D, Ströhl F, Meadows W, Ferry R, Dardov VJ, Tartaglia GG, Farrer LA, Kaminski Schierle GS, Kaminski CF, Holt CE, Fraser PE, Schmitt-Ulms G, Klenerman D, Knowles T, Vendruscolo M, St George-Hyslop P. FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions. Cell. 2018 Apr 19;173(3):720-734.e15.

Abstract

Reversible phase separation underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles and is, in part, driven by the intrinsically disordered low-complexity (LC) domain of FUS. Here, we report that cooperative cation-π interactions between tyrosines in the LC domain and arginines in structured C-terminal domains also contribute to phase separation. These interactions are modulated by post-translational arginine methylation, wherein arginine hypomethylation strongly promotes phase separation and gelation. Indeed, significant hypomethylation, which occurs in FUS-associated frontotemporal lobar degeneration (FTLD), induces FUS condensation into stable intermolecular β-sheet-rich hydrogels that disrupt RNP granule function and impair new protein synthesis in neuron terminals. We show that transportin acts as a physiological molecular chaperone of FUS in neuron terminals, reducing phase separation and gelation of methylated and hypomethylated FUS and rescuing protein synthesis. These results demonstrate how FUS condensation is physiologically regulated and how perturbations in these mechanisms can lead to disease.