Keio University discovers novel therapeutic target for ALS — Nuclear lamina and nucleoporin dysfunction

A research group led by Professor Hideyuki Okano of the Regenerative Medicine Research Center and Project Professor Daisuke Ito and Instructor Kensuke Okada of the Department of Neurology, School of Medicine at Keio University has announced that they successfully generated a novel mouse model of amyotrophic lateral sclerosis (ALS) using genome editing technology and discovered nuclear lamina and nucleoporin disruption as a novel therapeutic target. The model mice have a point mutation introduced at the position corresponding to the FUS gene abnormality found second most commonly in patients with familial ALS in Japan. Unlike conventional models, this discovery is expected to be useful for pathological analysis as a disease model physiologically closer to the patients. The results were published in the international journal Brain on September 24.

ALS is a progressive, intractable neurological disease that affects motor neurons, resulting in respiratory muscle impairment and death within a few years of onset. The nuclear lamina, which has a double-layered lamina structure, envelops the nucleus of a cell, stabilizing the nuclear structure and protecting the intranuclear DNA from external influences. The nucleoporin is a complex embedded in the nuclear lamina and serves as a channel for mass transport between the nucleus and the cytoplasm. Both the nuclear lamina and nucleoporins must function properly, or cell function will be severely impaired.

There have been several previous reports on nuclear laminas and nucleoporins in ALS, but their interpretation and significance have remained controversial. The model mice created in this study showed gait impairment and other motor disorders with age, which were associated with the loss of motor neurons, disruption of the nuclear lamina and nucleoporins, and DNA damage in spinal cord motor neurons. Nuclear lamina disruption was also observed in spinal cord motor neurons differentiated from iPS cells derived from patients with FUS-ALS. Furthermore, the disrupted nuclear lamina and nucleoporins were also confirmed in the postmortem tissue (spinal cord) of patients with ALS.

Therefore, the genome-edited mice replicating the genetic abnormalities in patients with ALS were shown to develop motor dysfunction with age, and disruption of the nuclear lamina and nucleoporins observed in these mice is the definitive pathogenic mechanism of ALS and a novel therapeutic target.

Okano said, "Previously, we generated and analyzed iPS cells from a patient with a mutation near the C-terminus of the FUS gene, which is associated with rapidly progressing type of familial ALS (2016). In this study, we created genetically engineered mice with a mutation introduced at the same position, and we were surprised by the fact that these mice had much milder symptoms than patients. I realized that even symptoms caused by the same genetic mutation can differ significantly between the species. Among them, nuclear lamina and nucleoporin disruption was the most prominent phenotype in the FUS mutant mice generated in this study. We believe this is an essential finding for ALS pathogenesis."

Journal Information
Publication: Brain
Title: Multiple lines of evidence for disruption of nuclear lamina and nucleoporins in FUS amyotrophic lateral sclerosis
DOI: 10.1093/brain/awae224