Studying the role of the nuclear lamina in age dependent demyelination

摘要 常染色体显性脑白质营养不良（ADLD）是一种致命的、进行性的成人发病疾病，其特征在于： 自主神经和运动功能障碍伴广泛CNS脱髓鞘。ADLD是唯一的 脑白质营养不良与一个专门的晚发病年龄，这表明机制，特别涉及年龄- 依赖的髓鞘调节受到影响。我们以前已经证明，ADLD是由复制引起的， 核纤层蛋白B1的表达增加，是核纤层蛋白B1基因表达增加的基础。 疾病过程。在真核细胞中，核纤层蛋白B1是核纤层（一种纤维网）的主要成分 与内核膜相邻。核纤层维持核的结构完整性 并在基本细胞过程中发挥作用，包括转录、DNA复制、DNA修复和 表观遗传调节核板层中的脱落细胞已被证明参与正常和 病理性衰老核纤层蛋白B1过表达增加与年龄依赖性 ADLD中的脱髓鞘未知。为了解决这些问题，我已经产生了转基因（TG）小鼠， LMNB 1过表达模型靶向CNS中的特定细胞类型。含核纤层蛋白B1的TG-LMNB 1小鼠 靶向少突胶质细胞（在CNS中产生髓鞘的细胞类型）的过表达显示出惊人的 年龄依赖性运动功能障碍、肌无力和瘫痪，使人联想到ADLD中的症状 患者 具体目标1将阐明病理生理学途径的基础ADLD，使用表型和组织学， TG-LMNB 1小鼠中年龄依赖性神经变性的病理学测定。TG-LMNB 1中的运动功能 将在不同年龄评估小鼠以确定症状的最早发作和时间 退化表型的进展。大脑和脊髓的组织病理学分析 我们来确定所涉及的结构和退化过程的性质，以及它如何演变， 时间具体目标2将检验核纤层蛋白B1控制基因的年龄依赖性失调 在少突胶质细胞中的表达和染色质修饰是ADLD的分子途径的基础。为 为此，我们将在CNS中进行RNA表达和核纤层蛋白B1-染色质相互作用的全基因组分析。 来自TG-LMNB 1与野生型小鼠。该项目将确定年龄依赖性 ADLD和核板层的神经变性。在未来，TG-LMNB 1小鼠可用于开发 ADLD的治疗方法了解ADLD的基础可以提供以下见解 常见疾病（多发性硬化症）中的脱髓鞘和连接核板层的细胞过程 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.