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

描述（由申请人提供）：我们先前的研究表明，在肌萎缩性侧索硬化症（ALS）小鼠模型中，肌肉神经衰弱发生在症状发作前约2-3个月。在我们的初步研究中，我们发现，符合这种早期的神经衰弱，超微结构的变化发生在整个运动神经元（MN）从神经肌肉突触前末梢到远端树突。我们建议识别和表征最早发生的病理变化，并确定它们发生的顺序，以区分起始事件和继发事件。我们的总体假设是，系统检查和表征与初始去神经支配相关的早期事件将提供对导致MN功能障碍的疾病机制的深入了解。ALS是一种最衰弱的神经退行性疾病，其根本原因和病理生理学尚不清楚。因此，没有显著改善或延迟疾病进展的治疗，并且在诊断后3-5年内发生由呼吸衰竭导致的死亡。以前的研究集中在并发症或症状发作和MN变性后发生的病理事件。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发病机制的关键部位，但一些研究发现，外周（PNS）事件可能在临床症状方面引发疾病，并且CNS中的支持性胶质细胞也参与疾病病理。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开始得太晚，或者因为靶向机制在导致运动神经元死亡的级联事件中太远。最近的研究表明，突变型SOD 1-FALS小鼠的发病机制已经改变了ALS是一种细胞体疾病，伴有轴突和突触继发性丧失的传统观点。现在，在该领域有一个越来越多的共识，即轴突和突触是第一个退化的细胞部位。然而，关于（1）轴突和突触丧失是在这些位点还是由细胞体、非神经元细胞甚至非MN中的病理学引发的，以及（2）ALS中介导轴突/突触丧失的具体分子机制在很大程度上是未知的，仍然存在争议。为了研究这些问题，我们提出了以下具体目标：目标1：为了确定突变SOD 1G 93 A小鼠PNS症状发作前发生的事件。目的2：鉴定突变型SOD 1G 93 A小鼠CNS中症状发作前发生的事件。目的3：确定在其他运动神经元疾病模型中症状发作前是否发生类似事件。总之，我们建议的主要目标是阐明启动和介导轴突/突触损失的具体机制，通过描述疾病的发病机制，并确定预防轴突/突触损失的策略。通过这种方式，我们希望为运动神经元疾病和其他涉及轴突和突触早期丧失的神经退行性疾病的治疗开辟新的途径。

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.