The role of Lamin B1 in myelin maintenance and demyelination

脱髓鞘和髓鞘形成障碍病症包括人类中的大量退行性病症，包括多发性硬化症。最近，髓鞘参与精神疾病，如精神分裂症也被提出。了解髓磷脂是如何合成和正确维持的是一项具有挑战性的任务，几十年来一直在进行深入研究。然而，我们对这些过程的了解仍然有限，并且缺乏对大多数脱髓鞘/髓鞘形成障碍疾病的有效治疗。成人型常染色体显性脑白质营养不良（ADLD）是一种缓慢进展的神经系统疾病，其特征是CNS中对称性广泛髓鞘丢失，表型与慢性进展性多发性硬化症（MS）相似。我们最近发现了导致ADLD的基因组重复。患者携带核纤层蛋白基因的额外拷贝，核纤层蛋白B1，导致ADLD脑组织中基因剂量增加。核纤层蛋白B1在果蝇中的表达增加导致退化表型。此外，当培养的细胞过度表达这种蛋白质时，异常的核形态是明显的。这是第一个人类疾病归因于核纤层蛋白B1突变。核纤层蛋白B的抗体存在于自身免疫性疾病中，它也是一种被单克隆抗体J1-31识别的抗原，该单克隆抗体J1-31针对从MS患者脑中解剖的斑块而产生。这就提出了可能性，它可能与自身免疫性攻击发生在MS.在这个补助金中，我们建议研究的表达模式和调节的核纤层蛋白B1奠定基础，为未来的调查机制，核纤层蛋白B1调节适当的髓鞘维护。我们已经建立了表达不到四个额外LMNB 1基因拷贝的BAC和cDNA转基因小鼠模型。我们也在产生条件（泰特调控下）过表达小鼠模型的过程中。这些小鼠的特征将提供深入了解的机制，不仅为ADLD的病理生理学，但也为髓鞘生物合成。此外，我们确定了miR-23作为核纤层蛋白B1的负调节因子。我们拟采用原代培养和共培养的方法研究Lamin B1和miR-23在少突胶质细胞发育和髓鞘形成中的作用。这些知识将产生对核纤层蛋白B1过表达导致脱髓鞘的途径的见解。了解这种脱髓鞘疾病的机制可能提供线索的途径，调节获得性脑白质营养不良的表达。最终，这些知识将为髓鞘的合成和维持提供新的见解，并确定开发治疗干预措施的新靶点，以刺激MS等常见疾病的髓鞘再生。

Demyelinating and dysmyelinating disorders include a large number of degenerative conditions in humans including Multiple Sclerosis. Recently, myelin involvement in psychiatric disorders such as schizophrenia was also suggested. Understanding how myelin is synthesized and properly maintained is a challenging task that has been under intense investigation for decades. However, our knowledge of these processes is still limited and effective treatments for most of the demyelinating/dysmyelinating diseases are absent. Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive, neurological disorder characterized by symmetrical widespread myelin loss in the CNS, with a phenotype similar to chronic progressive multiple sclerosis (MS). We have recently identified a genomic duplication that causes ADLD. Patients carry an extra copy of the gene for the nuclear lamina protein, Lamin B1, resulting in increased gene dosage in ADLD brain tissue. Increased expression of Lamin B1 in Drosophila resulted in a degenerative phenotype. In addition, an abnormal nuclear morphology was apparent when cultured cells over-expressed this protein. This is the first human disease attributable to Lamin B1 mutations. Antibodies to Lamin B are found in autoimmune diseases and it is also an antigen recognized by a monoclonal antibody, J1-31, raised against plaques dissected from MS patient brains. This raises the possibility that it may be linked to the autoimmune attack that occurs in MS. In this grant, we propose to study the expression pattern and regulation of Lamin B1 to lay a foundation for future investigation into the mechanism by which Lamin B1 regulates proper myelin maintenance. We have generated BAC and cDNA transgenic mouse models that express less than four extra copies of LMNB1 genes. We are also in the process of generating conditional (under tet regulation) overexpression mouse models. Characterization of these mice will provide insight into the mechanisms not only for ADLD pathophysiology but also for myelin biogenesis. In addition, we identified miR-23 as a negative regulator of Lamin B1. We propose to use primary culture and co-culture methods to study the effect of Lamin B1 and miR-23 in oligodendrocyte development and myelination. Such knowledge will yield insights into pathways through which Lamin B1 overexpression leads to demyelination. Understanding the mechanism of this demyelinating disorder may provide clues to pathways that modulate the expression of acquired leukodystrophies. Ultimately, this knowledge will provide new insight in the synthesis and maintenance of myelin and identify novel targets for developing therapeutic interventions for stimulating remyelination in common disorders like MS.