Energy metabolism in motor neuron diseases

Motor neuron diseases (MNDs) are a group of fatal neurodegenerative disorders. They are characterised by the death of motor neurons, the neurons which carry the electrical information from the spinal cord to the muscles, which results in progressive paralysis. The two most common MNDs are the childhood-onset spinal muscular atrophy (SMA) and the adult-onset amyotrophic lateral sclerosis (ALS). There is no effective treatment for most forms of MNDs, including ALS, a disease with a lifetime risk of 1 in 400. Therefore, there is an urgent need to identify new therapeutic targets that will span across the range of MNDs.
In order to function, all cells need energy, which is derived from food in various forms such as sugars (e.g. glucose), fat (lipids) or protein. The numerous processes occurring in the body which allow the generation of energy usable by the cell from nutrients is called energy metabolism. Metabolism is the keystone of cellular function and optimal metabolism has been associated with longevity whilst metabolic pathway dysregulation has been linked with numerous diseases, such as cancer, heart failure, but also neurodegenerative disorders. The human brain is estimated to consume ~20 % of the total body energy supply, whilst it only represents 2 % of body weight. This highlights the major metabolic requirement of the brain and more generally of the central nervous system (brain and spinal cord). My hypothesis is that the spinal cord is energy starved and that sustaining cellular energy could represent a promising therapeutic strategy.
To evaluate my hypothesis, I will study the metabolism in two mouse models of MNDs, a model of ALS and a model of SMA. This side-by-side analysis will allow identification of common changes, hence identification of more robust therapeutic targets. Finally, validation of these targets in patients' samples will be key to increase translation potential. My first objective will be to assess metabolism in these two mouse models across organs at multiple time points and across multiple organs before the clinical signs start and as the signs progress using varied techniques such as untargeted mass spectrometry and assays to evaluate mitochondrial function, the powerhouse of the cell. Looking at multiple organs is important, as although the main clinical signs relate to spinal cord disease, pathological changes have been identified in other organs in MND patients. Overall, this objective will allow identification of the critical point when metabolism switch occurs and is key to evaluate the importance of metabolic changes to disease progression. My second objective will look in greater depth at spinal cord metabolism. Indeed, the spinal cord is not only composed of neurons of various types but also of a more abundant population of cells called the glial cells. These cells have various subtypes but they overall play a key role in the support and maintenance of neuronal function. Surprisingly, the exact role of these glial cells in normal spinal cord metabolism is poorly known. Using state-of-the-art mass spectrometry imaging, I will assess the relative contribution of glial cells and neurons into the overall spinal cord metabolism in normal mice and in MND mice. I anticipate this will allow a better understanding of why some neurons within the spinal cord are more susceptible to the disease than others. Finally, the changes identified in the first two objectives will be confirmed on patients' derived samples of SMA and ALS. This is key to confirm the relevance of these pathways to human pathology. Subsequently, the main targets will then be brought forward and their therapeutic potential will be evaluated by testing whether modulating these metabolic pathways can help reverse the pathological changes in patient derived cell cultures of MNDs. Ultimately, the aim of this project is to identify and confirm common targets across MNDs, from which we can design new therapies.

Motor neuron diseases are a group of neurodegenerative disorders ranging from childhood Spinal Muscular Atrophy (SMA) to adult-onset Amyotrophic Lateral Sclerosis (ALS). They are characterised by the progressive degeneration of motor neurons, almost invariably resulting in paralysis and premature death. Despite differences in their age of onset and genetic causes, SMA and ALS share many commonalities and their side-by-side study could prove invaluable to identify new therapeutic targets.
Changes in bioenergetic pathways have been described in patients and animal models of ALS and SMA, although their direct potential for therapeutic targeting remains under-explored. I hypothesise that dysregulation in energetic pathways such as glycolysis and oxidative phosphorylation precede neuromuscular changes and that glial cells, the supporters of neuronal function, play a key role in spinal cord metabolic changes. Finally, I anticipate that manipulating these metabolic pathways could be a much-needed therapeutic strategy.
To test these hypotheses, I will study changes in the metabolome and in mitochondrial function in mouse models of SMA and ALS across organs before and after disease onset. This will allow identification of the main metabolic changes alongside the key moment when metabolic switch occurs. I will also decipher the relative contribution of (motor) neurons and of glial cells in the spinal cord using state-of-the-art single-cell MALDI mass spectrometry imaging. The key findings from these animal models will then be validated on MND patients' samples, to confirm the relevance of these pathway dysregulations to human pathology, before evaluating the therapeutic potential of pathway manipulation in patients' cells models of MNDs. Ultimately, this proposal aims to identify new, much-needed, therapeutic targets.