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

ALS 小鼠模型中的运动神经元疾病：终结从何开始

• 批准号: 8653030
• 负责人: Carol Milligan
• 金额: $ 31.41万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8653030
• 关键词: Address; Adult; Amyotrophic Lateral Sclerosis; Animal Model; Axon; Axonal Transport; Axotomy; Biological Markers; Biology; Cells; Cessation of life; Clinical; Clinical Trials; Consensus; Data; Dendrites; Denervation; Development; Diagnosis; Disease; Disease Progression; Distal; Event; Functional disorder; Goals; Location; Mediating; Mitochondria; Modeling; Molecular; Morphology; Motor Neuron Disease; Motor Neurons; Mus; Muscle; Muscle Cells; Muscle Weakness; Muscle denervation procedure; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neuromuscular Junction; Neurons; Pathogenesis; Pathology; Patients; Peripheral; Peripheral Nervous System; Presynaptic Terminals; Research; Respiratory Failure; Role; Site; Spinal Cord; Swelling; Symptoms; Synapses; Therapeutic Intervention; Time; Translating; Treatment Efficacy; human disease; improved; injured; insight; interdisciplinary approach; mouse model; mutant; neuromuscular; neuronal cell body; patient oriented research; prevent; protein expression; public health relevance; reinnervation; research study; response

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.

描述（由申请人提供）：我们之前的研究表明，肌萎缩侧索硬化症 (ALS) 小鼠模型在症状出现前约 2-3 个月发生肌肉无力。在我们的初步研究中，我们发现与这种早期削弱相一致，从神经肌肉突触前末梢到远端树突的整个运动神经元（MN）都发生超微结构变化。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，以区分始发事件和继发事件。我们的总体假设是，系统检查和表征与初始去神经相关的早期事件将有助于深入了解导致 MN 功能障碍的疾病机制。 ALS 是一种最令人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，没有显着改善或延缓疾病进展的治疗方法，诊断后 3-5 年内就会因呼吸衰竭而死亡。之前的研究主要集中在症状出现和 MN 变性同时发生或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，但多项研究发现，外周（PNS）事件可能引发临床症状，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启动得太晚，或者是因为目标机制太落后于导致运动神经元死亡的级联事件。最近对突变 SOD1 FALS 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丧失的细胞体疾病。现在该领域越来越多的共识认为轴突和突触是第一个细胞退化部位。然而，关于以下方面仍存在争议：（1）轴突和突触丢失是否是在这些部位引发的，还是由细胞体、非神经元细胞甚至非 MN 中的病理引起的；（2）介导 ALS 中轴突/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，我们提出以下具体目标： 目标 1：确定突变型 SOD1G93A 小鼠 PNS 症状出现前发生的事件。目标 2：确定突变 SOD1G93A 小鼠中枢神经系统症状出现前发生的事件。目标 3：确定其他运动神经元疾病模型在症状出现之前是否发生类似事件。总之，我们建议的主要目标是通过描述疾病发病机制来阐明启动和介导轴突/突触损失的具体机制，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途径。

项目成果

Characterization of early pathogenesis in the SOD1(G93A) mouse model of ALS: part II, results and discussion.

• DOI: 10.1002/brb3.142
• 发表时间: 2013-07
• 期刊: Brain and behavior
• 影响因子: 3.1
• 作者: Vinsant S;Mansfield C;Jimenez-Moreno R;Del Gaizo Moore V;Yoshikawa M;Hampton TG;Prevette D;Caress J;Oppenheim RW;Milligan C
• 通讯作者: Milligan C

Characterization of early pathogenesis in the SOD1(G93A) mouse model of ALS: part I, background and methods.

• DOI: 10.1002/brb3.143
• 发表时间: 2013-07
• 期刊: Brain and behavior
• 影响因子: 3.1
• 作者: Vinsant S;Mansfield C;Jimenez-Moreno R;Del Gaizo Moore V;Yoshikawa M;Hampton TG;Prevette D;Caress J;Oppenheim RW;Milligan C
• 通讯作者: Milligan C