ALS related metabolic pathway discovered by Sheffield scientists using Biolog technology


Sheffield, UK and Hayward, CA, USA –February 13, 2019–Researchers at the University of Sheffield have identified a new pathway that is disrupted in amyotrophic lateral sclerosis (ALS), a debilitating and ultimately lethal motor neuron disease (MND). The discovery was enabled by converting skin cells to brain cells called astrocytes and comparing the energy metabolism of cells taken from ALS versus normal controls, using a new metabolic phenotyping technology developed by Biolog, Inc, a California biotech company. The scientists discovered the loss of a key enzyme that could have major consequences for how the central nervous system copes with aging, stress and loss of energy metabolism. Details of the discovery are published in the March issue of the journal “Brain”.

ALS, also known as Lou Gehrig’s Disease, is an adult onset disorder involving loss of motor neurons that control skeletal muscles. At some point in a patient’s life, their motor neurons start to die leading to muscle wasting and eventually death – typically within 2 years post diagnosis. Disruption of the ability of central nervous system cells to produce energy is thought to be a major contributing factor to the disease and could influence disease progression rates. The disease kills six people every day in the UK and there is no cure.

The Sheffield scientists led by Dr Scott Allen, Dr Laura Ferraiuolo, and Professor Dame Pamela Shaw, used a method previously developed by Drs Ferraiuolo and Meyer in the USA to take skin cells from patients, reprogram them into brain cells, and observe them to identify novel pathways of metabolic dysfunction. This has never been done before. Working in collaboration with the US-based company Biolog, Inc., a world leader in cell analysis, they employed a metabolic scanning technology to look for and find differences in the metabolism of astrocytes from ALS patients. Astrocytes are star-shaped brain cells that play a key role in supporting motor neurons by acting as a crucial source of energy nutrients in the central nervous system.

Dr. Allen who is a Motor Neurone Disease Association funded Senior Research Fellow at the Sheffield Institute for Translational Neuroscience (SITraN), found that the cells from ALS patients had reduced ability to convert a metabolic substrate called adenosine into energy due to loss of a key enzyme called adenosine deaminase. The consequence of this loss could be a toxic build-up of adenosine in the CNS and subsequent loss of inosine production. Inosine is a metabolic intermediate that is generally protective to neuronal cells. Until now, the link between ALS and inosine production through the loss of adenosine deaminase had not been made. As further confirmation, Dr. Allen fed the ALS astrocytes inosine, and found that energy production increased and the patient’s astrocytes became more supportive towards motor neurons, helping them live longer.

“We are really excited about this set of results as no one has implicated adenosine deaminase in ALS before” commented Dr. Allen. “Our results indicate that the higher the level of adenosine deaminase the greater the protection against adenosine mediated toxicity and the greater support towards motor neurons when given inosine. Although we are at an early stage, I think approaches aimed at increasing adenosine deaminase levels, combined with inosine supplementation has the potential to slow down disease progression in ALS patients and improve the quality of life. Altering the level of adenosine deaminase by gene therapy has previously been shown to be beneficial and safe in patients suffering from severe combined immunodeficiency disease. Further, inosine is a safe and readily-available nutritional supplement, which has been successfully tested in Parkinson’s disease patients. However, further testing in the laboratory will need to be performed. We have had fantastic support from our charitable funders, Neurocare and the Motor Neurone Disease Association, as well as technical support from Biolog. I am looking forward to following up on these exciting results”.

According to Dr. Barry Bochner, Biolog’s CEO, “the Biolog cell analysis technology was developed with the intent of providing scientists with a new approach for comparing normal versus disease cells to look for differences that could underlie the deficiencies. Credit goes to Dr. Allen and his colleagues for being one of the first to set up an excellent cell model and then employ the Biolog technology strategically.”

About The University of Sheffield
The University of Sheffield is one of the world’s leading universities and a member of the UK’s prestigious Russell Group of leading research-led institutions. Sheffield has six Nobel Prize winners among former staff and students and its alumni go on to hold positions of great responsibility and influence all over the world, making significant contributions in their chosen fields. Global research partners and clients include Boeing, Rolls-Royce, Unilever, AstraZeneca, Glaxo SmithKline, Siemens and Airbus, as well as many UK and overseas government agencies and charitable foundations. Within the University, SITraN is an international centre of excellence for basic to applied research in neurodegenerative diseases. Since its opening by her Majesty the Queen in 2010, SITraN has developed into a leading global facility which is at the forefront of research and expertise, pioneering new treatments for neurodegenerative diseases and bringing new hope to patients and families across the UK. The £18 million center houses state-of-the-art laboratories and equipment, including a clinical database of over 1,500 patients and a vital resource of human brain-bank material.