Scientists identify new, disrupted pathway in motor neuron disease

Researchers at the University of Sheffield have identified a new, disrupted pathway in motor neuron disease (MND), a discovery that could pave the way for new treatments.

Innovative discoveries were discovered by converting skin cells into brain cells called astrocytes and comparing energy metabolism of cells taken from patients with MND compared to healthy controls, using a new metabolic phenotyping technology developed by Biolog, Inc., a California biotechnology company.

Scientists at the Institute of Translational Neuroscience (SITRAN) at the University of Sheffield have discovered the loss of a key enzyme that could have major consequences on how the central nervous system copes with aging, stress and loss of energy metabolism.

MND, also known as amyotrophic lateral sclerosis (ALS), is a disease that occurs in adulthood and leads to the loss of motoneurons controlling skeletal muscle. At some point in a patient's life, his motor neurons begin to die, resulting in muscle wasting and eventually death, usually within two years of diagnosis.

Disruption of the central nervous system's ability to create energy is considered a major contributor to the disease and may affect rates of disease progression. Six people die every day from the disease in the UK and there is currently no cure.

Sheffield scientists led by Dr. Scott Allen, Dr. Laura Ferraiuolo and Professor Dame Pamela Shaw of SITRAN used a method previously developed by Dr. Ferraiuolo and Dr. Meyer in the United States to collect skin cells from patients, reprogram them into brain cells and observe them. identify new pathways of metabolic dysfunction, which has never been done before.

Working in collaboration with the American company Biolog, Inc., a world leader in cell badysis, they used a metabolic scanning technology to research and find differences in astrocyte metabolism of MND patients. Astrocytes are star – shaped brain cells that play a key role in supporting motor neurons by acting as a crucial source of energy in the central nervous system.

Dr. Allen, a senior researcher funded by the Motor Neurone Disease Association, has discovered that MND patient cells have a reduced ability to turn into energy the metabolic substrate called adenosine due to the loss of a key enzyme called adenosine deaminase.

The consequence of this loss could be a toxic accumulation of adenosine in the central nervous system and a subsequent loss of inosine production, a generally protective metabolic intermediate. Until now, the link between the production of MND and inosine by the loss of adenosine deaminase has not been established. When Dr. Allen fed brain astrocytes into inosine, energy production increased and the patient's astrocytes became more favorable to motor neurons, helping them to live longer.

"We are really excited about this set of results because no one had yet involved adenosine deaminase in the DMN," said Dr. Allen.

"Our results indicate that the higher the level of adenosine deaminase, the higher the protection against adenosine – induced toxicity and the higher the motor neuron support is when inosine is administered.

"Although we are at an early stage, I think that increasing levels of adenosine deaminase, combined with inosine supplementation, could slow the progression of the disease in patients with MND." , many additional tests must be performed in the laboratory. "

"We had fantastic support from Biolog and the work would not have been possible with funding from Neurocare and the Motor Neurone Disease Association, and I look forward to following these interesting results."

It has already been shown that altering the level of adenosine deaminase by gene therapy was beneficial and safe for patients with severe combined immunodeficiency. Inosine is a safe and readily available nutritional supplement that has been successfully tested in patients with Parkinson's disease. We can therefore hope that in the future, this combination of treatments could work in people with MND, improving their quality of life and helping them to live longer.

Barry Bochner, President and CEO of Biolog, said, "Biolog's cell badysis technology has been developed to provide scientists with a new approach to compare normal cells to diseased cells in order to look for differences underlying deficiencies.

"Dr. Allen is one of the first to have set up an excellent cell model, and then to use Biolog technology strategically."

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University of Sheffield