Autosomal-dominant leukodystrophy (ADLD) is a rare fatal neurodegenerative disorder with overexpression of the nuclear lamina component, Lamin B1 due to LMNB1 gene duplication or deletions upstream of the gene. The molecular mechanisms responsible for driving the onset and development of this pathology are not clear yet. Vacuolar demyelination seems to be one of the most significant histopathological observations of ADLD. Considering the role of oligodendrocytes, astrocytes, and leukemia inhibitory factor (LIF)-activated signaling pathways in the myelination processes, this work aims to analyze the specific alterations in different cell populations from patients with LMNB1 duplications and engineered cellular models overexpressing Lamin B1 protein. Our results point out, for the first time, that astrocytes may be pivotal in the evolution of the disease. Indeed, cells from ADLD patients and astrocytes overexpressing LMNB1 show severe ultrastructural nuclear alterations, not present in oligodendrocytes overexpressing LMNB1. Moreover, the accumulation of Lamin B1 in astrocytes induces a reduction in LIF and in LIF-Receptor (LIF-R) levels with a consequential decrease in LIF secretion. Therefore, in both our cellular models, Jak/Stat3 and PI3K/Akt axes, downstream of LIF/LIF-R, are downregulated. Significantly, the administration of exogenous LIF can partially reverse the toxic effects induced by Lamin B1 accumulation with differences between astrocytes and oligodendrocytes, highlighting that LMNB1 overexpression drastically affects astrocytic function reducing their fundamental support to oligodendrocytes in the myelination process. In addition, inflammation has also been investigated, showing an increased activation in ADLD patients’ cells.

常染色体显性脑白质营养不良 (ADLD) 是一种罕见的致命性神经退行性疾病，由于 LMNB1 基因重复或该基因上游缺失，导致核纤层成分 Lamin B1 过度表达。导致这种病理发生和发展的分子机制尚不清楚。空泡脱髓鞘似乎是 ADLD 最重要的组织病理学观察结果之一。考虑到少突胶质细胞、星形胶质细胞和白血病抑制因子 (LIF) 激活的信号通路在髓鞘形成过程中的作用，本工作旨在分析来自 LMNB1 重复患者和过表达 Lamin B1 蛋白的工程细胞模型的不同细胞群中的具体变化。我们的结果首次指出，星形胶质细胞可能在疾病的演变中发挥关键作用。事实上，来自 ADLD 患者的细胞和过度表达 LMNB1 的星形胶质细胞显示出严重的超微结构核改变，而过度表达 LMNB1 的少突胶质细胞中不存在这种改变。此外，星形胶质细胞中核纤层蛋白 B1 的积累会导致 LIF 和 LIF 受体 (LIF-R) 水平降低，从而导致 LIF 分泌减少。因此，在我们的两种细胞模型中，LIF/LIF-R 下游的 Jak/Stat3 和 PI3K/Akt 轴均下调。值得注意的是，给予外源性 LIF 可以部分逆转 Lamin B1 积累引起的毒性作用，但星形胶质细胞和少突胶质细胞之间存在差异，这突出表明 LMNB1 过表达会极大影响星形胶质细胞的功能，从而减少星形胶质细胞在髓鞘形成过程中对少突胶质细胞的基本支持。此外，还对炎症进行了研究，结果显示 ADLD 患者细胞的激活增加。