Molecular basis for neurodegeneration and dementia in motor neurone disease/amyotrophic lateral sclerosis (MND/ALS)

Background: Motor neurone disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a severe neurodegenerative disorder characterized by progressive atrophy and weakness of the bulbar, limb and respiratory muscles. Most cases of MND (>90%) are sporadic, but there are also genetic mechanisms implicated in the causation of a subset of cases. There are no effective biomarkers for sporadic MND and so ante-mortem diagnosis is mainly clinical. The molecular basis for dementia associated with sporadic MND is little understood and no effective disease-modifying therapies have been developed for it.
Aims To employ our multi-omic methodology: to analyse post-mortem brain tissue from cases of MND with and without dementia, and matched controls without evidence of brain disease; and to compare the results with those for dementia caused by Alzheimer’s disease and Huntington’s disease.

Feasibility: We recently discovered that highly-impacted brain regions in Huntington’s disease (Patassini et al 2016) and Alzheimer’s disease (Xu et al 2016a, b) have toxic concentrations of glucose, fructose and urea. These defects reflect an impairment of central pathways of energy metabolism, including the glycolytic and polyol pathways, the TCA cycle and urea metabolism. These levels are equivalent to those that cause neurodegeneration in the context of diabetes (Freeman et al 2016) and so we expect that these defects may well be amenable to interventions similar to those for diabetes; an example supporting this reasoning is provided by a 2017 Lancet report of a successful trial of the anti-diabetic molecule, ‘exenatide’ in Parkinson’s disease. No comparable studies of the metabolic status of the brain have been undertaken so far in ALS.

Expected Outcomes We expect that this PhD programme will lead to major new insights concerning the molecular basis of neurodegeneration and dementia in MND and that these findings will guide development of new interventions aimed at these novel metabolic defects.

Training/techniques to be provided -
The student will develop skills across a range of ‘omics disciplines and the underlying biochemistry necessary to describe/interpret the molecular basis of neurodegenerative diseases and progression to dementia. The student will learn quantitative skills as applied in the analysis (by chromatography/mass spectrometry) of human brain in neurodegeneration and dementia through: metallomics (inductively coupled plasma mass spectrometry); metabolomics (gas-chromatography-mass spectrometry and liquid-chromatography-mass spectrometry); and proteomics (liquid-chromatography-mass spectrometry). Datasets between groups will be compared using Bayesian statistics. The principals and practice of advanced analytical chemistry/metabolite quantification for elucidation of disease mechanism will be emphasized, since all aspects of this project will be driving towards developing a novel/informative model for the causation of MND-evoked dementia. [112 words]