The role of Lamin B1 in myelin maintenance and demyelination

脱髓鞘和髓鞘障碍包括人类的大量退行性疾病，包括多发性硬化症。最近，髓鞘也被认为与精神分裂症等精神疾病有关。了解髓鞘是如何合成和正确维持的是一项具有挑战性的任务，几十年来一直处于紧张的研究之下。然而，我们对这些过程的了解仍然有限，大多数脱髓鞘/髓鞘障碍疾病缺乏有效的治疗方法。成人起病常染色体显性遗传性白质营养不良(ADLD)是一种进展缓慢的神经系统疾病，其特征是中枢神经系统对称性广泛的髓鞘丢失，其表型类似于慢性进行性多发性硬化症(MS)。我们最近发现了一种导致ADLD的基因组复制。患者携带核层蛋白Lamin B1的额外基因拷贝，导致ADLD脑组织中基因剂量增加。果蝇中Lamin B1的表达增加导致了退化的表型。此外，当培养细胞过度表达该蛋白时，核形态明显异常。这是第一种可归因于Lamin B1突变的人类疾病。抗Lamin B的抗体在自身免疫性疾病中被发现，它也是一种被针对MS患者大脑解剖斑块的单抗J1-31识别的抗原。这增加了它可能与多发性硬化症中发生的自身免疫攻击有关的可能性。在这项研究中，我们建议研究Lamin B1的表达模式和调控，为进一步研究Lamin B1调节适当的髓鞘维持的机制奠定基础。我们已经建立了表达不到四个额外LMNB1基因拷贝的BAC和cDNA转基因小鼠模型。我们还在建立条件性(在TET调控下)过表达的小鼠模型。这些小鼠的特征将不仅为ADLD的病理生理学，也为髓鞘的生物发生机制提供深入的见解。此外，我们还发现miR-23是Lamin B1的负调控因子。我们建议使用原代培养和共培养的方法来研究Lamin B1和miR-23在少突胶质细胞发育和髓鞘形成中的作用。这些知识将有助于深入了解Lamin B1过度表达导致脱髓鞘的途径。了解这种脱髓鞘障碍的机制可能会为调节获得性脑白质营养不良的表达提供线索。最终，这些知识将为髓鞘的合成和维持提供新的见解，并确定新的靶点，用于开发刺激MS等常见疾病的重新髓鞘形成的治疗干预措施。

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.