Understanding the molecular pathogenesis of clinical heterogeneity in motor neuron disease

About the project

Substantial heterogeneity exists in the clinical presentation of MND with disease progression varying from months to decades and variable non-motor symptoms including cognitive and behavioural dysfunction in as many as 50% of patients. Due to this substantial clinical heterogeneity patients face prognostic uncertainty and stratification for clinical trials is difficult.

The aim is to implement cutting-edge genetic, transcriptomic and proteomic approaches to probe pathogenic variations in individuals with MND using post-mortem brain tissue. Using these techniques, we have been able to identify (i) cell-type specific and (ii) brain region-specific differences in key pathways that may account for regional susceptibilities to the disease process in individuals with MND. These findings, combined with access to linked clinical records will hopefully allow us to continue to explore clinico-pathological correlations with the aim of identifying therapeutic targets and developing biomarkers necessary for clinical trials in this field.

Publication(s)

Gregory JM, McDade K, Livesey MR, et al.
Spatial transcriptomics identifies spatially dysregulated expression of GRM3 and USP47 in amyotrophic lateral sclerosis. 2020;46(5):441-457.
Neuropathol Appl Neurobiol
2020 Jan 10
Gregory JM, McDade K, Bak TH, et al.
Executive, language and fluency dysfunction are markers of localised TDP-43 cerebral pathology in non-demented ALS.
J Neurol Neurosurg Psychiatry
2019 Sep 12
Mehta AR, Selvaraj BT, Barton SK, et al.
Improved detection of RNA foci in C9orf72 amyotrophic lateral sclerosis post-mortem tissue using BaseScopeā„¢ shows a lack of association with cognitive dysfunction.
Brain Communications
2020 Aug 31

Primary location

Edinburgh

Principal Investigator

Other people involved

Dr Elizabeth Elliott (Clinical research fellow)

Olivia Rifai (PhD student)

Dr Arpan Mehta (Clinical research fellow)

Dr Bhuvaneish T Selvaraj (PI)

Prof Sharon Abrahams (PI)

Prof Colin Smith (PI)

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