Sheffield Institute for
Translational Neuroscience


Good cells turn bad

Good cells turn bad: supportive brain cells which 'go-rogue’ and become destructive could hold the key to MND

A pioneering study has revealed a cell which usually supports motor neuron function becomes destructive and actually causes cell death in patients with motor neurone disease (MND).

Oligodendrocytes are large cells whose main function is to produce myelin. Myelin wraps around the neurons and allows signals to run faster, thus facilitating the communication from one neuron to another. Here in green we managed to capture the wide myelin tree that develops from the central cell body. In MND these cells gain toxic properties and from friends they become enemies.MND2.png

An international team of scientists found the usually supportive oligodendrocyte brain cell plays an essential role in the progression of the degenerative disease.

The researchers, led by Dr Laura Ferraiuolo from the Sheffield Institute of Translational Neuroscience (SITraN), made the ground breaking discovery after developing a novel oligodendrocyte in vitro model from the skin cells of MND patients.

The study also showed that reducing levels of SOD-1, a gene which has been linked to causing MND, can rescue the adverse effect on motor neurons.

Dr Ferraiuolo, a Lecturer in Translational Neurobiology at the University of Sheffield, began the research at The Kaspar Laboratory based at the Centre for Gene Therapy at the Research Institute at Nationwide Children’s Hospital (RINCH) in Columbus, Ohio, as part of her EU-funded Marie Curie Fellowship.

“This is the first human in vitro model allowing us to study the specific interaction between neurons and oligodendrocytes from MND patients,” said Dr Ferraiuolo.

“The ability to model the communication between the cells dying during the disease, the motor neurons, and their surrounding neighbouring cells is crucial for the development and timing of the therapies.

“With this rapid reprogramming protocol, we are a step closer to personalised medicine.”

Previous studies suggest that other human cells which support motor neurons, such as astrocytes and microglia, contribute to motor neuron death in MND. This breakthrough comes from observations in both mouse and human oligodendrocytes made possible by a revolutionary technique, ‘the direct conversation’ method, developed by Professor Brian Kaspar and his team at the Kaspar Laboratory.

The ‘direct conversation’ method allows skin cells from living MND patients to be programmed into neural progenitor cells, which have the potential to be differentiated into different types of cells such as astrocytes, oligodendrocytes and neurones. During this study, neural progenitor cells were differentiated into oligodendrocytes, which were derived from skin cells collected from both patients with familial MND, those with a family history of the disease, and sporadic MND.

The results of the study, published today (27 September 2016) in the journal Proceedings of the National Academy of Sciences (PNAS), showed that oligodendrocytes from both familial and sporadic MND patients result in motor neuron death.

Oligodendrocytes from healthy individuals or from those suffering from other neuromuscular disorders, such as Becker muscular dystrophy did not harm motor neurons – indicating the specific phenotype to MND derived oligodendrocytes.

Professor Kaspar, senior author of the paper and principal investigator in Columbus, said: “By using this novel direct conversational method, in the past few years we have been able to interrogate the function of different glial cells in MND and we have started understanding that different supporting cells ‘go-rogue’ at different stages of the disease and contribute to the pathology through different mechanisms.”