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Brighton & Sussex Medical School



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

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

Diagnosis of ALS/MND is based on clinical examination and as yet there are no robust markers of diagnosis or disease progression that can be used in the clinic or in clinical trials. A major thrust of current research is to identify such markers (‘biomarkers’) in body fluids such as blood and/or cerebrospinal fluid (CSF). In this porject, we are using a new method that we have developed to catalogue a group of molecules known as non-coding ribonucleic acids (ncRNAs) in the blood and CSF of ALS patients and healthy individuals. We will then identify those ncRNAs which show significant changes in the patients’ blood and/or CSF in comparison with the healthy controls. Next, we will examine up to 10 of the most promising ncRNAs, which consistently show higher (or lower) levels in the patients’ blood and/or CSF, singly or in combination to validate their use as ‘biomarkers’. Any new ncRNA biomarkers resulted from this study should permit earlier diagnosis, assist in drug development through discovery of new disease mechanisms, and act as indicators of early responses to potential new treatments, thus helping us to accelerate advances towards the goal of halting disease progression at an earlier stage of its evolution than is possible at present. 

Thomson AG, et al., Extracellular vesicles in neurodegenerative disease - pathogenesis to biomarkers. Nature Reviews Neurology 2016, 2:346-57.

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.