Motor Neuron Disease in Mouse Models of ALS: Where Does The End Begin

描述(由申请人提供)：我们以前的研究表明，在肌萎缩侧索硬化症(ALS)小鼠模型中，肌肉神经支配发生在症状出现前大约2-3个月。在我们的初步研究中，我们发现，与这种早期的神经支配相一致，从神经肌肉突触前终末到远端树突的整个运动神经元(MN)都发生了超微结构的变化。我们建议识别和描述发生的最早的病理变化，并确定它们发生的顺序，以区分起始事件和继发性事件。我们的总体假设是，对与初始失神经相关的早期事件的系统检查和表征将提供对导致MN功能障碍的疾病机制的洞察。肌萎缩侧索硬化症是一种最具破坏性的神经退行性疾病，其根本原因和病理生理学尚不清楚。因此，没有任何治疗方法可以显著改善或延缓疾病的发展，在确诊后3-5年内会发生因呼吸衰竭而导致的死亡。以前的研究主要集中在同时发生的或在症状出现和MN变性之后发生的病理事件。多年来，研究一直集中在脊髓和中枢神经系统(CNS)中的MN细胞体，作为ALS发病的关键部位，但一些研究发现，外周(PNS)事件可能从临床症状方面引发疾病，CNS中的支持性胶质细胞也参与了疾病的病理。许多ALS临床试验都没有成功，可能是因为治疗在疾病过程中启动得太晚，或者是因为靶向机制在导致运动神经元死亡的一系列事件中太远了。最近关于突变型SOD1fals小鼠疾病发病机制的研究修正了ALS的传统观点，即ALS是一种继发性轴突和突触丢失的细胞体疾病。现在，该领域越来越多的人达成共识，认为轴突和突触是变性的第一个细胞部位。然而，(1)轴突和突触的丢失是在这些部位开始的，还是由细胞体、非神经元细胞甚至非MN的病理引起的；(2)ALS轴突和突触丢失的具体分子机制在很大程度上尚不清楚。为了研究这些问题，我们提出了以下具体目标：目标1：确定突变的SOD1G93A小鼠PNS在症状出现之前发生的事件。目的2：确定突变型SOD1G93A小鼠中枢神经系统在症状发生前发生的事件。目的3：确定在其他运动神经元疾病模型中，类似的事件是否在症状出现之前发生。综上所述，我们建议的主要目标是通过描述疾病的发病机制来阐明启动和介导轴突/突触丢失的具体机制，并确定预防轴突/突触丢失的策略。通过这种方式，我们希望为运动神经元疾病和其他神经退行性疾病的治疗开辟新的途径，这些疾病涉及轴突和突触的早期丧失。

DESCRIPTION (provided by applicant): Our previous studies indicate that muscle enervation occurs approximately 2-3 months prior to symptom onset in the mouse model of amyotrophic lateral sclerosis (ALS). In our preliminary studies, we find that coincident with this early enervation, ultrastructual changes occur throughout the motoneurons (MNs) from neuromuscular presynaptic terminal to distal dendrites. We propose to identify and characterize the earliest pathological changes that occur and to determine the order in which they occur to distinguish initiating events from secondary events. Our overall hypothesis is that systematic examination and characterization of early events associated with initial denervation will provide insight into disease mechanisms resulting in MN dysfunction. ALS is a most debilitating neurodegenerative disease whose underlying causes and pathophysiology are not understood. As a result, there is no treatment that significantly ameliorates or delays the progression of the disease, and death resulting from respiratory failure occurs within 3-5 years from diagnosis. Previous studies have focused on pathological events that occur co-incident or after symptom onset and MN degeneration. For many years, research has centered on the MN cell body in the spinal cord and central nervous system (CNS) as the key site of pathogenesis in ALS, but several studies have found that peripheral (PNS) events may initiate the disease in terms of clinical symptoms, and supportive glial cells in the CNS are also involved in disease pathology. Numerous ALS clinical trials have been unsuccessful, perhaps because the treatments are initiated too late in the course of the disease or because the targeted mechanisms are too far down the cascade of events that leads to motor neuron death. Recent studies characterizing disease pathogenesis in mutant SOD1 FALS mice have revised the traditional view of ALS as a disease of the cell body with secondary loss of axons and synapses. There is now a growing consensus in the field that the axon and synapses are the first cellular sites of degeneration. However, there is still controversy over (1) whether axon and synapse loss is initiated at those sites or by pathology in the cell body, in non-neuronal cells or even in non-MNs and (2) the specific molecular mechanisms mediating axon/synapse loss in ALS are largely unknown. To investigate these issues we are proposing the following specific aims: Aim 1: To identify the events that occur before symptom onset in the mutant SOD1G93A mouse PNS. Aim 2: To identify the events that occur before symptom onset in the mutant SOD1G93A mouse CNS. Aim 3: To determine if similar events occur before symptom onset in other models of motoneuron disease. In summary, the major goals of our proposal are to elucidate the specific mechanisms that initiate and mediate axon/synapse loss by describing disease pathogenesis and to identify strategies for preventing axon/synapse loss. In this way we hope to open up new avenues for the treatment of motor neuron disease and other neurodegenerative diseases that involve early loss of axons and synapses.