Scientists identify a cause and possible route to treat the fatal motor neuron disease condition ALS

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Swansea University academic Professor William Griffiths is the co-lead in groundbreaking research which has discovered a method to identify a cause of the motor neuron disease ALS (Amyotrophic Lateral Sclerosis), more quickly and proposed a potential approach to treatment.

In 2014, the debilitating and fatal disorder ALS came into the limelight with the Ice Bucket Challenge. ALS, also known as Lou Gehrig’s disease, attacks the nerve cells. There is no cure for ALS.

Prof Griffiths and Dr Yuqin Yang

A team of researchers, lead by Professor William Griffiths of the Swansea University Medical School and Professor Martin Turner of the University of Oxford, have published the results of their study which shows for the first time, that people with ALS have higher levels of cholesterol in the fluid surrounding the brain than people without the disease. The researchers propose in the study that a potential therapeutic approach for ALS treatment could be using drugs that reduce the levels of cholesterol in the brain.


ALS typically starts with twitching of muscles and ultimately leads to paralysis and respiratory failure. About 5,000 people in the UK and 20,000 in the USA have this disease at any given time. Riluzole, the only drug for ALS approved by the U.S. Food and Drug Administration, has been in the market since 1995 and shows only modest slowing of progression in a fraction of patients. There is no current treatment that stops or reverses ALS.

The researchers investigated if targeting cholesterol was an option for ALS treatment. Earlier studies indicated that an increase in cholesterol caused oxidative stress that led to neuronal death in ALS. Secondly, a gene critical for cholesterol metabolism (called CYP27A1) was identified as a susceptibility gene that increased a person's likelihood of contracting ALS.

Some studies indicated that statins, drugs that reduce cholesterol, exacerbated ALS. However, a 2013 study definitively showed that the detrimental effects of statins were abolished when adjusted for age of onset and body mass index.

“In the light of these studies, and considering that about 25 percent of the body’s cholesterol is present in brain, it seemed like cholesterol might be a potential target for ALS studies,” says Professor Griffiths.

ALS research graphic larger The investigators used serum, a clear liquid separated from clotted blood, from 35 ALS patients and 24 healthy individuals, and cerebrospinal fluid, a colourless fluid surrounding the brain and spinal cord, from 20 ALS patients and 15 healthy individuals for the study. They measured cholesterol and its metabolites by mass spectrometry. Their analysis of the serum showed no significant differences in cholesterol or most of its metabolites between people with ALS and healthy individuals of a similar age. However, the researchers observed that the level of cholesterol was higher in the cerebrospinal fluid (CSF), which surrounds the brain and spinal cord, of the people with ALS.

Prof Griffiths and his team, which included Dr Yuqin Wang also from the Swansea University Medical School, explained this observation by pointing to the greater number of neurons that die during ALS. The dying neurons release more cholesterol from their membranes, and the metabolic pathways are unable to remove this excess cholesterol.

“We think that people with ALS are unable to dispose of cholesterol from the brain efficiently, leading to the presentation of the disease” explains Griffiths. Griffiths is optimistic that “not only will our work provide a method to diagnose ALS but be useful to stratify people for more efficient clinical trials and could also provide a route to development of a new drug to treat ALS.” 

The research paper “Defective cholesterol metabolism in amyotrophic lateral sclerosis” has been published in the Journal of Lipid Research (JLR) and highlighted in ASBMB Today, the magazine of the American Society for Biochemistry and Molecular Biology. Prof Griffiths and Dr Wang presented their data at the recent ALS/MND symposium in Dublin.

Link to the JLR article-

Picture: Professor William Griffiths and Dr Yuqin Wang, Swansea University

Graphic: Life and death of motor neurons.