UCL Queen Square Institute of Neurology


Scientific 'dream team' shed light on motor neuron death

29 May 2018

A new study from the Francis Crick Institute, involving UCL Institute of Neurology researchers, has uncovered the earliest events of pathogenesis in amyotrophic lateral sclerosis (ALS).

Crick researchers

Established in summer 2016, the Francis Crick Institute (or ‘the Crick’) is a unique partnership between the Medical Research Council (MRC), Cancer Research UK, Wellcome, UCL, Imperial College London and King’s College London.

At the Crick, Dr Rickie Patani (Wellcome Trust Clinician and Scientist and Group Leader, UCL Institute of Neurology) and his lab collaborated with Professor Jernej Ule (also at IoN), Dr Raphaëlle Luisier, and Professor Nick Luscombe (also at UCL Genetics Institute) to investigate why motor neurons die in patients with ALS.

ALS, also known as motor neuron disease, is a progressive neurodegenerative disease which causes the death of neurons controlling voluntary muscles. People with ALS progressively lose their ability to move, eat, speak and breathe.

Previous studies have suggested a link between ALS and deregulation of RNA – a molecule that has a vital role in coding, decoding, regulating and expressing genes.

Working with Professor Ule, an expert in RNA, Dr Patani’s lab used cutting edge stem cell technology to take skin cells from healthy volunteers and from patients with ALS, turning them into stem cells.

Using specific chemical signals, they ‘guided’ the stem cells into becoming motor neurons that they could study in the lab. This generated substantial RNA sequencing data from healthy and diseased motor neurons at different stages of disease progression. Bioinformaticians Professor Luscombe and Dr Raphaëlle Luisier then analysed the data.

"Initially, using conventional analysis, we didn't detect any differences in RNA sequencing between healthy and diseased motor neurons," Dr Luisier told the Crick. "But we knew something must have been going wrong to make the ALS motor neurons die, so we wrote a new program to dig deeper into the genetic code - and when the results came back, we knew we were on to something."

Their analysis demonstrated that in ALS motor neurons, parts of the RNA sequence that don’t code for proteins weren’t being effectively cut out before the RNA was translated into protein. The team then discovered that ALS motor neurons were losing a protein called SFPQ which normally resides inside the cell nucleus.

The loss of SFPQ was evident in human stem cell and animal models of hereditary ALS, and in post-mortem-tissue of non-hereditary ALS.

As Honorary Consultant Neurologist at the National Hospital for Neurology and Neurosurgery (NHNN), Dr Patani sees first hand ALS’s impact on patients.

Rickie said, "Now that we know these key events are linked to motor neuron death in people with ALS, we can start to think about how we could develop new ways to detect and treat the disease."

The study was helped by all researchers working together at the Crick.

Professor Ule said, "The project was going well even when we were working in different institutes in London, but being able to chat to each other almost every day speeds things up dramatically. We finished the project within a year, while it might have taken two years or more if we weren't all here at the Crick.”
Dr Patani added, “These links to world class translational neuroscience and our fantastic clinical ALS service at NHNN have been crucial here.”



From left: Prof Nick Luscombe, Dr Rickie Patani, Raphaelle Luisier and daughter Agnes (on screen), Guilia Tyzack and Prof Jernej Ule

Source: The Crick

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