Scientists identify a cause and possible route to treat ALS

A team of researchers, lead by Professor William Griffiths of Swansea University Medical School and Professor Martin Turner of the University of Oxford, have published the results of a study that shows for the first time people with ALS (Amyotrophic Lateral Sclerosis) have higher levels of cholesterol in the fluid surrounding the brain than people without the disease (Swansea University, 2016). The researchers propose that a potential therapeutic approach to ALS treatment could be using drugs that reduce the levels of cholesterol in the brain.

ALS, also known as Lou Gehrig’s disease, attacks the nerve cells. It typically starts with twitching of the muscles and ultimately leads to paralysis and respiratory failure. About 5,000 people in the UK and 20,000 in the US have ALS at any given time. Riluzole, the only drug for ALS approved by the FDA, has been in the market since 1995 and shows only a modest slowing of the progress of the disease in a fraction of patients. There is currently no 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 which 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. Professor Griffiths said “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.”

The investigators used serum from thirty five ALS patients and twenty four healthy individuals and cerebrospinal fluid from twenty ALS patients and fifteen healthy individuals. They measured cholesterol and its metabolites by mass spectrometry. Their analysis of the serum showed no significant differences in cholesterol or most of the metabolites between people with ALS and healthy individuals of a similar age. However, the researchers observed the level of cholesterol was higher in the cerebrospinal fluid, a colourless fluid which surrounds the brain and spinal cord, of the people with ALS.

Professor Griffiths and his team 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. Professor Griffiths said “We think that people with ALS are unable to dispose of cholesterol from the brain efficiently, leading to the presentation of the disease…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. Professor Griffiths and his colleague Dr Yuqin Wang, also from Swansea University Medical School, presented their data at the recent ALS/MND symposium in Dublin.

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