Scientists Uncover Cell Mechanism That Plays Key Role In Amyotrophic Lateral Sclerosis (ALS)

Scientists have discovered a mechanism that causes defects in a group of brain cells that is key to the development of ALS, or Lou Gehrig's disease. 

The researchers hope the discovery will lead to a new target for treating this and other neurodegenerative diseases that may share a similar cause.

ALS is a disease that gradually destroys brain cells that control muscle movement.

The research team at the Ken and Ruth Davee Department of Neurology at Northwestern University in Chicago, IL, reports the findings in the journal Cerebral Cortex.

Amyotrophic lateral sclerosis (ALS) first came to public attention when an American baseball player called Lou Gehrig died of the disease in 1941.

ALS is a disease that gradually destroys motor neurons - the brain cells that control muscle movement - leading to increasing muscle weakness, impaired speech, problems with swallowing and breathing, and eventually paralysis and death.

ALS progresses at different speeds in different people - the average life expectancy after diagnosis is between 2 and 5 years.

Study explains why upper motor neurons are vulnerable to degeneration

In earlier work, the research team had established the important role of upper motor neurons - a small group of neurons in the brain - in the development of ALS.

In this latest study, the research team begins to explain why this group of neurons - which makes up only about 150,000 of the 2 billion cells in the brain - is vulnerable to degeneration.

They developed a new mouse model for studying upper motor neurons, and found that increasing stress in the endoplasmic reticulum (ER) is one cause of upper motor neuron death. The ER is a cell component that serves as a site for making proteins and lipids.

The new model is a breed of mice that lack the UCHL1 gene. Previous studies have linked mutations in this gene to motor defects in human patients. Using cell cultures and the new mouse model, the team found that loss of UCHL1 protein function affects protein regulation pathways, ER stress and upper motor neuron survival.

Commenting on the finding, the research team says:

"Now that we appreciate the importance of upper motor neurons, we need to develop therapies that improve their survival. This study gives us a target to go after, bringing us one step closer to building effective treatment strategies."

Findings could have implications for Parkinson's, Alzheimer's

The research team says while other types of brain cell vastly outnumber upper motor neurons, their function is vital.

"They act as the spokesperson of the brain by collecting, integrating, translating and transmitting the brain's message to the spinal cord targets, and by doing so they initiate and modulate voluntary movement."

Previously, scientists believed spinal motor neurons were more important in ALS and that upper motor neurons played a secondary role.

The team believes the findings could also have applications to other neurodegenerative diseases partly caused by ER stress, including Parkinson's disease and Alzheimer's disease.

ALS was in the headlines more recently when videos of the ALS Association's Ice Bucket Challenge went viral on the internet in 2014. 

And in the more recent release of the film The Theory of Everything, we saw how physicist and cosmologist Stephen Hawking - who has been living with ALS for 50 years - and his wife met the challenges in the early years.

Another theory of how ALS develops is the framework destabilization hypothesis. This proposes the disease is triggered when the clean-up process inside brain cells cannot keep up with the rate at which waste is generated.

In October 2014, another team of researchers reported how increased protein instability may be a cause of ALS. The researchers found different mutations in a particular gene - SOD1 - might cause instability in SOD proteins, meaning they cannot fold properly and accumulate in brain cells faster than the clean-up process can cope with.

References:

1.     Corticospinal motor neurons are susceptible to increased ER stress and display profound degeneration in the absence of UCHL1 function, Hande Ozdinler, et al., Cerebral Cortex, doi:10.1093/cercor/bhu318, published online 16 January 2015.

2.     Northwestern University news release, accessed 29 January 2015.