Mechanism behind neuron death in motor neurone disease and frontotemporal dementia discovered

April 20, 2018, University of Cambridge
Mechanism behind neuron death in motor neurone disease and frontotemporal dementia discovered
Nerve cells. Credit: ColiN00B

Scientists have identified the molecular mechanism that leads to the death of neurons in amyotrophic lateral sclerosis (also known as ALS or motor neurone disease) and a common form of frontotemporal dementia.

Writing in Cell, the researchers from the University of Cambridge and University of Toronto also identify for these currently incurable diseases.

ALS is a progressive and terminal that damages the function of nerves and muscle, affecting 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.

A common characteristic of ALS and frontotemporal dementia is the build-up of clumps of misfolded RNA-binding proteins, including a protein called FUS, in the brain and spinal cord. This leads to the death of , which stops them from communicating with each other and from reaching the muscles.

FUS proteins can change back and forth from small liquid droplets (resembling oil droplets in water) to small gels (like jelly) inside . As the FUS protein condenses (from droplets to gel) it captures RNA and transfers it to remote parts of the neuron that are involved in making connections (known as synapses) with other neurons. Here, the protein 'melts' and releases the RNA. The RNA are then used to create new proteins in the synapses, which are essential for keeping the synapses working properly, especially during memory formation and learning.

In frontotemporal dementia and ALS, the proteins become permanently stuck as abnormally dense gels, trapping the RNA and making it unavailable for use. This damages nerve cells by blocking their ability to make the proteins needed for synaptic function and leads to the death of neurons in the brain and spinal cord.

In research funded by Wellcome, scientists used human cells that resembled neurons and neurons from frogs to investigate how the change in FUS from liquid droplets to small gels process is regulated and what makes it go awry. They found that this reversible process was tightly controlled by enzymes which chemically alter FUS making it able or unable to form droplets and gels. In frontotemporal dementia, the abnormal gelling was found to be caused by defects in the chemical modification of FUS. In motor neuron disease, it was caused by mutations in the FUS protein itself which meant it was no longer able to change form.

This research provides new ideas and tools to find ways to prevent or reverse the abnormal gelling of FUS as a treatment for these devastating diseases. Potential therapeutic targets identified by the researchers are the enzymes that regulate the chemical modification of FUS and the molecular chaperones that facilitate FUS proteins to change its form. These treatments would need to allow FUS to continue moving between safe reversible states ( and reversible gels) but prevent FUS from dropping into the dense, irreversible gel states that cause disease.

Professor Peter St George-Hyslop from the Cambridge Institute for Medical Research said: "This was a very exciting set of experiments where we were able to apply cutting edge tools from physics, chemistry and neurobiology to understand how the FUS normally works in nerve cells, and how it goes wrong in motor neurone disease and dementia. It now opens up a new avenue of work to use this knowledge to identify ways to prevent the abnormal gelling of FUS in and ."

Dr. Giovanna Lalli, from Wellcome's Neuroscience and Mental Health team, said: "Motor neurone disease and are devastating diseases that affect thousands of people across the UK, resulting in severe damage to the brain and . By bringing together an interdisciplinary team of researchers, this study provides important new insights into a fundamental process underlying neurodegeneration. Through their research, the team have uncovered promising new ways to tackle these diseases."

Explore further: Researchers describe mechanism of protein accumulation in neurodegenerative diseases

More information: Seema Qamar et al. FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions, Cell (2018). DOI: 10.1016/j.cell.2018.03.056

Related Stories

Researchers describe mechanism of protein accumulation in neurodegenerative diseases

April 20, 2018
Ludwig-Maximilians-Universitaet (LMU) in Munich researchers have characterized the mechanism that initiates the pathological aggregation of the protein FUS, which plays a central role in two distinct neurodegenerative diseases.

Changing size of neurons could shed light on new treatments for motor neurone disease

March 5, 2018
New research published in The Journal of Physiology improves our understanding of how motor nerve cells (neurons) respond to motor neurone disease, which could help us identify new treatment options.

Research reveals atomic-level changes in ALS-linked protein

January 18, 2018
For the first time, researchers have described atom-by-atom changes in a family of proteins linked to amyotrophic lateral sclerosis (ALS), a group of brain disorders known as frontotemporal dementia and degenerative diseases ...

Breakthrough discovery in cause of motor neurone disease and dementia

April 18, 2016
In an international study led by Dr Kelly Williams and Associate Professor Ian Blair from the Faculty of Medicine and Health Sciences at Macquarie University, researchers have linked the cause of two seemingly unrelated diseases: ...

Researchers close to understanding 'disease mechanisms' of ALS

March 8, 2018
Syracuse University researchers are making strides in understanding the disease mechanism of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.

The toxic relationship between ALS and frontotemporal dementia

February 5, 2018
ALS and frontotemporal dementia (FTD) are two neurodegenerative diseases with a toxic relationship, according to a new USC Stem Cell study published in Nature Medicine.

Recommended for you

Research shows signalling mechanism in the brain shapes social aggression

October 19, 2018
Duke-NUS researchers have discovered that a growth factor protein, called brain-derived neurotrophic factor (BDNF), and its receptor, tropomyosin receptor kinase B (TrkB) affects social dominance in mice. The research has ...

Good spatial memory? You're likely to be good at identifying smells too

October 19, 2018
People who have better spatial memory are also better at identifying odors, according to a study published this week in Nature Communications. The study builds on a recent theory that the main reason that a sense of smell ...

How clutch molecules enable neuron migration

October 19, 2018
The brain can discriminate over 1 trillion odors. Once entering the nose, odor-related molecules activate olfactory neurons. Neuron signals first accumulate at the olfactory bulb before being passed on to activate the appropriate ...

Scientists discover the region of the brain that registers excitement over a preferred food option

October 19, 2018
At holiday buffets and potlucks, people make quick calculations about which dishes to try and how much to take of each. Johns Hopkins University neuroscientists have found a brain region that appears to be strongly connected ...

Gene plays critical role in noise-induced deafness

October 19, 2018
In experiments using mice, a team of UC San Francisco researchers has discovered a gene that plays an essential role in noise-induced deafness. Remarkably, by administering an experimental chemical—identified in a separate ...

Weight loss success linked with active self-control regions of the brain

October 18, 2018
New research suggests that higher-level brain functions have a major role in losing weight. In a study among 24 participants at a weight-loss clinic, those who achieved greatest success in terms of weight loss demonstrated ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.