Lamin B1 overexpression increases nuclear rigidity in autosomal dominant leukodystrophy fibroblasts.

The architecture and structural mechanics of the cell nucleus are defined by the nuclear lamina, which is formed by A- and B-type lamins. Recently, gene duplication and protein overexpression of lamin B1 (LB1) have been reported in pedigrees widi autosomal dominant leukodystrophy (ADLD). However, how the overexpression of LB1 affects nuclear mechanics and function and how it may result in pathology remain unexplored. Here, we report diat in primary human skin fibroblasts derived from ADLD patients, LB1, but not other lamins, is overexpressed at die nuclear lamina and specifically enhances nuclear stiffness. Transient transfection of LB1 in HEK293 and neuronal N2a cells mimics die mechanical phenotype of ADLD nuclei. Notably, in ADLD fibroblasts, reducing LB1 protein levels by shRNA knockdown restores elasticity values to diose indistinguishable from control fibroblasts. Moreover, isolated nuclei from ADLD fibroblasts display a reduced nuclear ion channel open probability on voltage-step application, suggesting diat biophysical changes induced by LB1 overexpression may alter nuclear signaling cascades in somatic cells. Overall, die overexpression of LB1 in ADLD cells alters nuclear mechanics and is linked to changes in nuclear signaling, which could help explain die padiogenesis of diis disease. [ABSTRACT FROM AUTHOR]