Studying the role of the nuclear lamina in age dependent demyelination

摘要 常染色体显性遗传性脑白质营养不良(ADLD)是一种致命的进行性成人发病疾病，其特征是 自主神经和运动功能障碍伴广泛的中枢神经系统脱髓鞘。ADLD是独一无二的 脑白质营养不良完全是起病年龄较晚的，这表明与年龄有关的机制- 依赖髓鞘的调节受到影响。我们之前已经证明了ADLD是由重复引起的 LMNB1基因，它编码层蛋白B1，而层蛋白B1的表达增加是导致 疾病过程。在真核细胞中，层蛋白B1是核层的主要成分，核层是一种纤维网络 与内核膜相邻。核层维持细胞核的结构完整性。 在基本的细胞过程中发挥作用，包括转录、DNA复制、DNA修复和 表观遗传调控。核层的异常已被证明与正常和 病理性衰老。层蛋白B1过度表达与年龄相关性的机制 ADLD中的脱髓鞘现象尚不清楚。为了解决这些问题，我培育了转基因(TG)小鼠 LMNB1高表达的模型靶向CNS中的特定细胞类型。含层粘连蛋白B1的Tg-LMNB1小鼠 针对少突胶质细胞(在中枢神经系统中产生髓鞘的细胞类型)的过度表达显示出惊人的 年龄依赖性运动功能障碍、肌肉无力和瘫痪使人想起ADLD的症状 病人。 具体目标1将利用表型和组织学方法阐明支持ADLD的病理生理途径。 Tg-LMNB1小鼠年龄依赖性神经退行性变的病理分析。TG-LMNB1的运动功能 将在不同的年龄对小鼠进行评估，以确定最早出现症状的时间和时间 退行性表型的进展。对大脑和脊髓的组织病理学分析将使 我们来确定所涉及的结构和退化过程的性质，以及它是如何演变的 时间到了。特定目标2将检验与年龄相关的Lamin B1控制基因调节失调的假说 少突胶质细胞的表达和染色质修饰是ADLD发生的分子机制。为 因此，我们将在全基因组范围内分析中枢神经系统中RNA的表达和层蛋白B1与染色质的相互作用 来自TG-LMNB1和野生型小鼠。这个项目将确定年龄依赖之间的机械联系 ADLD和核板的神经变性。在未来，TG-LMNB1小鼠可以用于开发 ADLD的治疗方法。了解ADLD的基础可能有助于深入了解 常见疾病(多发性硬化症)的脱髓鞘和连接核层的细胞突起 和衰老。

Abstract Autosomal Dominant Leukodystrophy (ADLD) is a fatal, progressive adult-onset disease characterized by autonomic and motor dysfunction with widespread CNS demyelination. ADLD is unique among leukodystrophies with an exclusively late age of onset, suggesting that mechanisms specifically involving age- dependent myelin regulation are affected. We have previously shown that ADLD is caused by duplications of the LMNB1 gene, which encodes lamin B1, and that increased expression of lamin B1 underlies the disease process. In eukaryotic cells, lamin B1 is a major constituent of the nuclear lamina, a fibrous meshwork adjacent to the inner nuclear membrane. The nuclear lamina maintains the structural integrity of the nucleus and has roles in essential cellular processes including transcription, DNA replication, DNA repair, and epigenetic regulation. Abnormalities in the nuclear lamina have been shown to be involved in both normal and pathological aging. The mechanisms linking increased lamin B1 over-expression to age-dependent demyelination in ADLD are unknown. To address these questions, I have generated transgenic (TG) mouse models with LMNB1 over-expression targeted to specific cell types in the CNS. TG-LMNB1 mice with lamin B1 over-expression targeted to oligodendrocytes (the cell types that produce myelin in the CNS) show striking age-dependent motor dysfunction, muscle weakness and paralysis reminiscent of symptoms seen in ADLD patients. Specific Aim 1 will elucidate pathophysiological pathways that underlie ADLD, using phenotypic and histo- pathological assays of age-dependent neurodegeneration in TG-LMNB1 mice. Motor function in TG-LMNB1 mice will be assessed at different ages to determine the earliest onset of symptoms and the temporal progression of the degenerative phenotype. Histo-pathological analysis of the brain and spinal cord will allow us to determine the structures involved and the nature of the degenerative process and how it evolves over time. Specific Aim 2 will test the hypothesis that age-dependent dysregulation of lamin B1-controlled gene expression and chromatin modification in the oligodendrocyte underlies molecular pathways for ADLD. For this, we will perform genome-wide analyses of RNA expression and lamin B1-chromatin interactions in CNS from TG-LMNB1 vs. wild-type mice. This project will identify mechanistic links between age-dependent neurodegeneration in ADLD and the nuclear lamina. In the future, TG-LMNB1 mice can be used to develop therapeutic approaches for ADLD. An understanding of the basis of ADLD may provide insight into demyelination in common diseases (Multiple Sclerosis) and into cellular processes that link the nuclear lamina and aging.