Energy metabolism in motor neuron diseases

运动神经元病是一组致死性神经退行性疾病。它们的特征是运动神经元的死亡，这些神经元将电信息从脊髓传递到肌肉，导致进行性瘫痪。两种最常见的MND是儿童期发作的脊髓性肌萎缩症（SMA）和成人发作的肌萎缩侧索硬化症（ALS）。大多数形式的MND没有有效的治疗方法，包括ALS，这种疾病的终生风险为1/400。为了发挥功能，所有细胞都需要能量，这些能量来源于各种形式的食物，如糖（如葡萄糖）、脂肪（脂质）或蛋白质。发生在体内的许多过程，允许细胞从营养物质中产生可用的能量，称为能量代谢。代谢是细胞功能的基石，最佳代谢与长寿有关，而代谢途径失调与许多疾病有关，如癌症、心力衰竭，还有神经退行性疾病。据估计，人类大脑消耗约20%的身体总能量供应，而它只占体重的2%。这突出了大脑和更普遍的中枢神经系统（大脑和脊髓）的主要代谢需求。我的假设是，脊髓是能量饥饿和维持细胞能量可能是一个有前途的治疗策略。为了评估我的假设，我将研究两个小鼠模型的MNDs，ALS模型和SMA模型的代谢。这种并行分析将允许识别常见变化，从而识别更稳健的治疗靶点。最后，在患者样本中验证这些靶点将是增加翻译潜力的关键。我的第一个目标将是评估这两个小鼠模型在多个时间点和多个器官中的代谢，在临床体征开始之前，以及随着体征的进展，使用各种技术，如非靶向质谱和测定来评估线粒体功能，细胞的动力。观察多个器官是重要的，因为尽管主要的临床体征与脊髓疾病有关，但在MND患者的其他器官中也发现了病理变化。总体而言，该目标将允许识别代谢转换发生时的临界点，并且是评价代谢变化对疾病进展的重要性的关键。我的第二个目标是更深入地研究脊髓代谢。事实上，脊髓不仅由各种类型的神经元组成，而且还由称为神经胶质细胞的更丰富的细胞群组成。这些细胞有各种亚型，但它们总体上在支持和维持神经元功能方面发挥关键作用。令人惊讶的是，这些神经胶质细胞在正常脊髓代谢中的确切作用知之甚少。利用最先进的质谱成像技术，我将评估正常小鼠和MND小鼠中神经胶质细胞和神经元对整个脊髓代谢的相对贡献。我预计这将有助于更好地理解为什么脊髓内的一些神经元比其他神经元更容易患上这种疾病。最后，前两个目标中确定的变化将在SMA和ALS患者的衍生样本中得到证实。这是确认这些途径与人类病理学相关性的关键。随后，将提出主要目标，并通过测试调节这些代谢途径是否有助于逆转患者来源的MND细胞培养物的病理变化来评估其治疗潜力。最终，该项目的目的是确定和确认MND的共同目标，从中我们可以设计新的疗法。

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.