Title: Fuelling Motor Neuron Diseases – A Systematic Study of Energy Metabolism in ALS and SMA.
Funder: The Academy of Medical Sciences

Abstract: Motor neuron diseases, ranging from childhood Spinal Muscular atrophy (SMA) to adult-onset Amyotrophic Lateral Sclerosis (ALS), are characterised by the progressive degeneration of motor neurons, almost invariably resulting in paralysis and premature death. Despite differences in age of onset and their genetic causes, SMA and ALS share many commonalities and side-by-side studies of these diseases could prove invaluable in the identification of new therapeutic targets. Changes in bioenergetic pathways have been described in patients and animal models of both ALS and SMA, although their direct potential for therapeutic targeting remains under-explored. Additionally, recent research has suggested that metabolic dysfunction may be present at a systemic level in ALS and SMA. Preliminary studies in the spinal cord of a mouse model of SMA confirmed metabolic changes with a decrease in lactate levels, and an increase in myo-inositol. This study will build on these results to assess the chronological relationship between metabolic changes and clinical progression in well-validated mouse models of SMA and ALS, using 1H-NMR extracts of multiple tissues and organs. Individual metabolic pathways (e.g. glycolysis, pentose phosphate pathway, myo-inositol metabolism) will then be dissected using enzymatic assays, western blots and qPCR. Ultimately, the study of metabolism in these neurodegenerative conditions could lead to the identification of new, much-needed, therapeutic targets.

Lay abstract: Motor neuron diseases (MND) are a group of devastating, ultimately fatal neurodegenerative disorders. MND patients have progressive muscle weakness and paralysis, caused by the death of motor neurons: the nerve cells, which carry information from the spinal cord to muscles. Loss of these cells stops messages reaching the muscles and leads to paralysis. Why these cells specifically die in MNDs is unknown. To function, the spinal cord needs energy, mainly in the form of sugar (glucose). When the spinal cord cannot process glucose correctly, this likely contributes to disease progression. MNDs are a spectrum of diseases that share an underlying biology characterised by specific death of motor neurons. Two of the most common MNDs are spinal muscular atrophy (SMA), a childhood-onset MND, and amyotrophic lateral sclerosis (ALS), an adult-onset MND. Despite differences in their age of onset and genetic causes, these diseases have many commonalities, and so a side-by-side study could offer a broader understanding of how energy processing is affected. In this project, we will use disease models of SMA and ALS to examine glucose use as well as different energy sources in the spinal cord and other organs. Energy processing might change as the disease progresses, therefore we will look at these organs before the disease begins, during symptoms of the disease, and at the end of the disease process. Ultimately, the project aims to identify a common target across MNDs in the form of energy processing, from which we can then design new therapies.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL