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Microscopic green and black image showing connection between neurones
Brighton & Sussex Medical School

Research

Research

Project Summaries for Sussex MND Care & Research Network

Amyotrophic lateral sclerosis (ALS; MND, motor neuron disease) is a progressive degenerative disease of motor neurons in the brain and spinal cord affecting about 4000 people each year in the UK. There is no cure for ALS and although genetic factors cause about 10% of cases, for most people the cause is unknown.

Project 1

Identification of non-coding RNA biomarkers from serum and cerebrospinal fluid for use as biomarkers in amyotrophic lateral sclerosis patients 

Diagnosis of ALS/MND relies on clinical judgement and investigations to exclude other conditions, a process that may delay diagnosis and therefore treatment for many months. It is also difficult in the individuals with MND to predict the speed at which the disease will progress. Therefore, finding an indicator (biomarker) of disease in blood will decrease delay in diagnosis, improve understanding of progression, and, because some biomarkers are also related to causation, facilitate development of new treatments. We have been working on identifying a group of molecules called non-coding RNA (ncRNA) in the blood of people with ALS as potential biomarkers. We have identified seven ncRNAs that allow us to predict if a sample is from people with ALS or not. However, these ncRNAs do not reflect the speed at which the disease will progress, so we need to search for ncRNA biomarkers that change over time so that we can both predict and track disease progression. This will be done with the use of ALS samples collected over the course of the disease that have been enrolled into a large clinical trial and crucially we will use machine learning techniques to identify complex patterns of changes in dysregulated ncRNAs. This will allow us to predict the behaviour of ALS more accurately, to understand key differences between people with ALS, to aid in treatment development, and hence to improve outcomes for people affected by ALS. 

This work is supported by the Motor Neurone Disease Association and the My Name'5 Doddie Association.

Joilin, G., Gray, E., Thompson, A. G., Bobeva, Y., Talbot, K., Weishaupt, J., Ludolph, A., Malaspina, A., Leigh, P. N., Newbury, S., Turner, M. R., & Hafezparast, M. (2020). Identification of a potential non-coding RNA biomarker signature for amyotrophic lateral sclerosis. Brain Communications, 2(1). Read more here >

Project 2

Is reduced cytoplasmic dynein function a cause and a risk factor of MND?

Why motor neurons die in ALS remains unknown. Motor neurons possess a very long extension, the axon, that enables them to contact muscle and control its movement. In axons, an intricate trafficking of cellular components occurs from the cell body of the motor neuron to the site of contact with the muscle (anterograde direction), and the other way round (retrograde direction). It has long been thought that defects of transport in the axon might underlie degeneration of motor neurons, especially for retrograde axonal transport. This is supported by the existence of changes in the dynein proteins, that are the molecular motors responsible for retrograde axonal transport, in rare cases of familial ALS. However, it remains unclear whether and how reduced dynein function can cause on its own, or facilitate, motor neuron disease. In this project, we generate mice with different levels of the dynein protein in motor neurons to study whether this provokes the disease. In parallel, we can determine whether mildly reducing dynein is able to exacerbate the degeneration of motor neurons in a mouse model with a mutation in an ALS-associated gene known as Fused in sarcoma (FUS). Moreover, we want to establish whether loss of dynein leads to abnormal accumulation of proteins found in brains of ALS patients. The completion of this project will help us to understand the role of dynein in ALS, and whether this enzyme should be targeted for future therapeutics.

Hafezparast M, et al., Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 2003, 300:808-12. 

Project 3

The Role of Microglia-released microRNA in ALS Pathology

Neuroinflammation is recognised as an important event in the progression of disease in patients with amyotrophic lateral sclerosis (ALS). As part of this process, resident immune cells of the central nervous system, known as microglia, are activated to release a number of proteins and chemicals which modulate the function of neighbouring motor neurons but at high levels can damage these cells. Our recent data show that cultured microglia also release a group of molecules known as microRNAs (miRNAs) with differential expression in non-activated versus activated states. Importantly, there is increasing evidence that miRNAs released from microglia play an important role in cell-to-cell communication by modulating gene expression in adjacent cells. There are, however, significant gaps in our knowledge about the identities of microglia-derived miRNA and their impact on motor neurons in the context of ALS pathology. This project will utilise both wild-type and mutant mouse models of ALS to address these gaps by identifying the miRNAs expressed by activated and non-activated microglia and to determine which of these miRNAs are released into the space outside of these cells, what effect this may have on motor neurons, and whether this may underpin ALS. 

This work is supported by the Ann Merriman Memorial Scholarship by the Motor Neurone Disease Association.

Christoforidou, E., Joilin, G., & Hafezparast, M. (2020). Potential of activated microglia as a source of dysregulated extracellular microRNAs contributing to neurodegeneration in amyotrophic lateral sclerosis. Journal of Neuroinflammation, 17, 135. Read more here >

BACKGROUND IMAGE FOR PANEL

MIROCALS

This is now closed to new participants. Results expected late 2021/early 2022.

MIROCALS is a clinical trial being led by Professor P Nigel Leigh (Director of Sussex MND care & research network) and Dr Gilbert Bensimon (University Hospital of Nimes).

MIROCALS aims to find a new treatment for amyotrophic lateral sclerosis (ALS) by testing the interleukin-2 (IL-2), a molecule that helps to regulate our immune system.

You can read more about the study at the MIROCALS website >

The MND Association have also created an information sheet about the study.