1: Multiple lines of evidence for disruption of nuclear lamina and nucleoporins in FUS-ALS.
Science of the Month - October 2024
Kensuke Okada, Daisuke Ito, Satoru Morimoto, Chris Kato, Yuki Oguma, Hitoshi Warita, Naoki Suzuki, Masashi Aoki, Junko Kuramoto, Reona Kobayashi, Munehisa Shinozaki, Masahito Ikawa, Jin Nakahara, Shinichi Takahashi, Yoshinori Nishimoto, Shinsuke Shibata, Hideyuki Okano
Amyotrophic lateral sclerosis (ALS) is a disease in which motor neurons are damaged, making motor functions such as standing and walking, as well as basic daily activities like speaking and eating, difficult. Within a few years of onset, respiratory movements essential for life are also impaired. We focused on the FUS (fused-in sarcoma) gene mutation ( FUS -H517D) in familial ALS in Japan and created a novel mouse model using the CRISPR-Cas9 genome editing system. This mouse model exhibited age-dependent motor dysfunction, a decrease in spinal motor neurons, and disruption of the nuclear lamina and nuclear pore complexes. Furthermore, we observed similar disruption of the nuclear lamina and nuclear pore complexes in spinal motor neurons differentiated from iPS cells derived from ALS patients with the same FUS -H517D mutation, as well as in postmortem tissues from these patients. This study demonstrated that the disruption of the nuclear lamina and nuclear pore complexes in spinal motor neurons is a critical pathogenic mechanism of ALS and a novel therapeutic target. By combining research materials such as genome-edited mice, iPS cells, and patient pathological specimens, we can deepen our understanding of the pathology of ALS and dramatically accelerate the development of therapeutic drugs. We will continue to devote our efforts to research that will lead to treatments for as many ALS patients as possible.
(Daisuke Ito, Department of Neurology, Class of '71; Kensuke Okada, equivalent to Class of '94)
2:Urinary biomarkers associated with pathogenic pathways reflecting histological findings in lupus nephritis
Arthritis & Rheumatology.
Kazuoto Hiramoto, Shuntaro Saito, Hironari Hanaoka, Jun Kikuchi, Hiroyuki Fukui, Akinori Hashiguchi, Katsuya Suzuki, Tsutomu Takeuchi and Yuko Kaneko.
The search for biomarkers that can predict the severity of renal tissue damage and renal prognosis in lupus nephritis is an urgent issue. In this study, to identify urinary biomarkers that reflect the characteristics and extent of individual renal histological findings in lupus nephritis, we performed a proteomic analysis to verify the correlation with renal tissue scores. First, through cluster analysis of renal histopathological scores, we extracted five tissue subgroups based on the correlations between the scores. Next, we extracted groups of urinary proteins that correlated with each tissue subgroup. Pathway analysis confirmed that these urinary protein groups reflect the pathology of their corresponding renal histopathological findings. We then searched for proteins within these groups that were strongly correlated with specific renal histopathological findings, which led to the identification of calgranulin B (S100A9), MCP-1, and IGFBP-5. Validation by ELISA measurement showed that the urinary concentrations of these three proteins could specifically predict the severity of active glomerular lesions, interstitial inflammatory cell infiltration, and interstitial fibrosis, respectively. Immunohistochemical staining showed that these proteins were localized within the lesions of their corresponding renal tissues. The urinary proteins identified in this study may be useful for predicting the severity of histological findings in lupus nephritis.
(Kazuoto Hiramoto, Department of Rheumatology and Collagen Disease, Class of '92)
Other Published Papers
1: Regeneration of Nonhuman Primate Hearts With Human Induced Pluripotent Stem Cell-Derived Cardiac Spheroids.
Circulation.
Kobayashi H, Tohyama S, Ohashi N, Ichimura H, Chino S, Soma Y, Tani H, Tanaka Y, Yang X, Shiba N, Kadota S, Haga K, Moriwaki T, Morita-Umei Y, Umei TC, Sekine O, Kishino Y, Kanazawa H, Kawagishi H, Yamada M, Narita K, Naito T, Seto T, Kuwahara K, Shiba Y, Fukuda K.