Understanding the pathogenesis of motor neuron disease: a spatial multi–omics approach

Background

Motor neuron disease (MND) is fatally progressive neurodegenerative disease with limited treatment options and poor prognosis. Disease progression is characterised by the selective degeneration of motor neurons resulting in denervation and muscle atrophy causing rapidly progressive paralysis and death within 18 months to 2 years of a diagnosis. The pathological mechanisms underlying the selective degeneration of motor neurons are widely debated and likely involve many diverse pathways such as aberrant protein misfolding and aggregation, oxidative damage and mitochondrial dysfunction, excitotoxicity, and inflammation. Furthermore, MND is considered to be a non-cell autonomous disorder, that is to say that the pathology does not originate in the motor neurons themselves, but instead originates in the motor neurons’ support cells, the neuroglia. The complex relationship between these cell types and the underlying reason for the selective vulnerability of motor neurons and certain brain regions in this process is, however, poorly understood.

Given the increasing accessibility of next generation sequencing, new techniques can be implemented to help elucidate the underlying pathological relationship between neuronal and glial cells in MND. One such technique is RNA sequencing; whereby, with suitable neural tissue from MND patients, as is available from the Edinburgh brain bank, transcriptomic data can be analyzed from diseased MND patients to provide information that can be compared to control tissue, potentially highlighting key underlying mechanisms. However, RNA sequencing of whole brain tissue is limited by (a) not providing cell-type specific information on gene expression, and (b) not relating gene expression data to region-specific differences in disease severity.

The laboratory of our collaborator, Joakim Lundeberg, at the SciLifeLab, has recently developed a technique, called spatial transcriptomics (ST; Stahl et al, 2016). ST has been developed as a modification of RNA sequencing to allow for the retention of spatial information with cellular resolution. In the ST technique, tissue is sectioned and placed on top of spatially barcoded mRNA capture probes to allow for high resolution imaging that is then integrated with RNA sequencing of the underlying spatially captured mRNA.

We propose here, for this DTP project in collaboration with the Lundeberg SciLifeLab at the Karolinska Institute, the development of unique capture probes that will be adapted to analyze the spatial methylome, further enriching the dataset. In collaboration with the Edinburgh Brain Bank (Director, Professor Colin Smith) this project will utilize deeply phenotyped post mortem brain tissue from MND patients (from a cohort collected by Professor of Neurology and Regenerative Medicine, Siddharthan Chandran) for which we have also generated whole genome sequence data. This project will, to our knowledge, be the first known application of the spatial methylome approach to MND neural tissue. Integrated analysis of spatial transcriptome and methylome data from several regions of MND patients’ brains, alongside whole genome sequencing data and in depth clinico-pathological correlation studies, will provide a rich dataset to advance understanding of the pathogenesis of MND.

Aims

To use a multi-omics approach to understand the differential cellular and regional vulnerabilities in motor neuron disease in order to (i) better understand molecular and cellular predispositions to motor neuron disease; (ii) identify candidate therapeutic and diagnostic targets, and (iii) to identify disease subtypes to facilitate stratified therapeutics in the future.

Training Outcomes

Quantitative Skills: Generating, managing, analyzing and integrating large –omics datasets.

Interdisciplinary Skills: Application of molecular pathology laboratory skills including tissue sectioning, imaging and staining. Further analysis of in depth clinico-pathological correlation studies to facilitate a stratified medicine approach.

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location:

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note you must apply to one of the projects and you are encouraged to contact the primary supervisor prior to making your application. Additional information on the application process if available from the link above.

For more information about Precision Medicine visit:

http://www.ed.ac.uk/usher/precision-medicine