Sheffield Institute for
Translational Neuroscience

Motor System Biology

Understanding the causes and disease mechanisms underlying all forms of MND and finding the cellular pathways associated with motor neuron injury is a key goal of our laboratory research in order to find the relevant targets for therapeutic intervention. Therapies which are known to alter the effects of these dysregulated biochemical pathways can then be tested in our cellular and in vivo models.

Currently, we have the greatest understanding of disease mechanisms in the subtype of MND caused by a faulty SOD1 gene, but this accounts for only 20% of inherited forms of MND and approximately 2% of all MND cases as a whole. We have gained important insights into the cell specific toxicity produced by the mutant SOD1 protein. These include oxidative stress and increased cell death signalling, altered production of cytoskeletal components and axonal transport, and defects in energy production and metabolism within neurons.

More recently, we have gained a greater understanding of disease mechanisms in other inherited forms of MND such as those caused by changes in the C9ORF72, TDP43 and FUS genes which all show alterations in RNA processing and metabolism.

Major projects at SITraN are currently investigating several aspects of motor neuron injury including mitochondrial function, axonal transport, oxidative defence, glial dysfunction and RNA metabolism.

Using gene expression profiling to identify therapeutic targets

Investigating changes in gene expression helps us to understand
the vulnerability of motor neurons by identifying biochemical pathways involved in motor neuron injury.

We can isolate individual motor neurons from our MND brain bank samples using laser capture microdissection equipment and investigate the differences in gene expression compared to healthy individuals. Special Gene Chips allow the simultaneous analysis of expression levels of more than 40,000 genes in a single sample.

This advanced microarray techno-logy pioneered by Dr Janine Kirby and Dr Paul Heath provides crucial information about the pathophysio-logy of MND and can reveal which genes and pathways are linked to a specific disease state, as well as susceptibility factors and changes occurring during the disease course.

These microarray analyses are subsequently performed in model systems to confirm the results obtained from human samples.

A new and even more sophisticated approach allowing us to interrogate gene expression in health and disease is the use of next generation sequencing (Illumina HiScan).

Understanding the transport system and transport defects within motor neurons

Due to their long axons, motor neurons are heavily reliant upon efficient intracellular transport. Dr Andy Grierson and Dr Kurt De Vos have established methods to accurately measure the axonal transport of cargoes such as mitochondria (the energy generating “batteries” within cells) in living neurons. Their results show that intracellular transport is altered in motor neuron injury, and they are beginning to identify the cellular changes which cause the transport alterations indicating a new therapeutic approach to improve the damaged transport system.




Investigating defects in gene-RNA-protein production chains

Genes are transcribed into a messenger RNA (mRNA) intermediate which is then further processed and serves as a template to produce proteins. Widespread changes in RNA processing and metabolism are now clearly recognised as a pathophysiological component triggering neurodegeneration in Huntington’s disease (HD), spinocerebellar ataxias (SCAs), spinal muscular atrophy (SMA) and major subtypes of MND.


As yet, the processes triggered by RNA dysregulation that lead to age-related and selective death of neurons remain poorly understood. Dr Guillaume Hautbergue and his team are currently developing a novel methodology to assess which of the aberrant RNAs are translated into proteins and how these lead to neurodegeneration in MND linked to C9orf72, TDP43 and FUS.

Find out more about RNA in dysregulation in MND and other neurodegenerative diseases from our News: Why RNA is crucial to our understanding of MND.

Review: Decoding the pathophysiological mechanisms that underlie RNA dysregulation in neurodegenerative disorders: a review of the current state of the art. Matthew J. Walsh, Johnathan Cooper-Knock, Jennifer E. Dodd, Matthew J. Stopford, Simeon R. Mihaylov, Janine Kirby, Pamela J. Shaw  and Guillaume M. Hautbergue. Neuropathol Appl Neurobiol. 2014 Oct 16.







Understanding disease progression - The role of non-neuronal cells such as astrocytes and microglia in motor neuron injury and its propagation

In MND, strikingly, motor neuron injury spreads from one group of damaged neurons to the neighbouring healthy motor neurons “like a slow bush fire”. Accordingly, the pattern of muscle weakness spreads in an anatomically logical fashion in many patients.

Increasing evidence points to a role of the non-neuronal glial cells, called astrocytes, oligodendrocytes and microglia, surrounding motor neurons, in the propagation of cell injury. Dr Jon Wood and Dr Robin Highley are investigating oligodendrocyte dysfunction in ALS using human pathological material and zebrafish models. Dr Laura Ferraiuolo is growing motor neurons and glial cells generated from patients’ skin cells to investigate underlying mechanisms which may involve the release of inflammatory or toxic mediator substances from these cells or the failure to provide supportive factors required for motor neuron health.