- NEWDr. Kawade (Assistant Professor) and Ms. Nagata (Technical Staff) joined to our lab.
Our Lab Group Photo in 2021.
This laboratory has started since 2013.
Our mission is to uncover the mechanisms of neurodegenerative disorder, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) to develop the viable therapy.
2021 Apr. / Dr. Kawade (Assistant Professor) and Ms. Nagata (Technical Staff) joined to our lab.
2021 Feb. / Ms. Maekawa won the poster presentation award in 2nd CIBoG retreat.
2021 Jan. / Our paper is now open in Acta Neuropathologica Communications.
2020 Nov. / Dr. Sobue won the oral presentation award in the 39th Annual Meeting of Japan Society for Dementia Research.
2020 Sep. / Our paper is now open in Cell Death & Disease.
2020 Jun. / Our collaborative paper with Liverpool Univ. (UK) is now open in EBioMeidicine.
Our Lab Group Photo in 2021.
In our Lab. Dr. Yamanaka, Ms. Maekawa and Dr. Sobue from the right.
In this study, we analyzed gene expression profiles of microglia isolated by magnetic activated cell sorting (MACS) from three mouse models for neurodegenerative diseases: AppNL-G-F/NL-G-F mice that display an amyloid pathology, rTg4510 mice with tauopathy, and SOD1(G93A) mice with motor neurodegeneration by RNA-sequencing. Despite robust neuroinflammation with microglial responses in all mouse models, AppNL-G-F/NL-G-F mice do not show neuronal death, whereas rTg4510 and SOD1(G93A) mice show a substantial loss of neurons. We found that the reduction of homeostatic microglial genes was correlated with severity of neurodegeneration, whereas DAM genes were uniformly upregulated in all mouse models. Moreover, in human precuneus with early AD pathology, reduced gene expressions of microglia and oligodendrocytes were observed, although DAM genes were not upregulated. Results from the present study indicate a correlation between glial phenotypes and severity of neurodegeneration, and also provide important resources to better understand the role of glial dysfunction in progression of Alzheimer's disease.
Sobue A, Komine O, Hara Y, Endo F, Mizoguchi H, Watanabe S, Murayama S, Saito T, Saido T, Sahara N, Higuchi M, Ogi T and Yamanaka K
"Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer’s disease."
Acta Neuropathol Commun (2021) 9: 1. DOI: 10.1186/s40478-020-01099-x
Dr. Sobue (left), who won the prize, and Prof. Dr. Yamanaka (right).
Saifullah MAB, Komine O, Dong Y, Fukumoto K, Sobue A, Endo F, Saito T, Saido TC, Yamanaka K, Mizoguchi H
"Touchscreen-based location discrimination and paired associate learning tasks detect cognitive impairment at an early stage in an App knock-in mouse model of Alzheimer's disease."
Mol Brain (2020) 13: 147.
We found that microtubule-related proteins (MRPs) and RNA-binding proteins (RBPs) co-aggregated with TDP-43. These two types of proteins sequestered TDP-43 through independent mechanisms; a liquid-liquid phase separation (LLPS) and an aggresome formation. Moreover, in sporadic ALS patients, approximately half of skein-like TDP-43 inclusions were co-localized with HDAC6, but round and granular type inclusion were not. Our findings suggest that two pathways (LLPS and aggresomes) independently induce TDP-43 aggregation and that both the mechanisms are involved in TDP-43 pathology in sporadic ALS patients. The findings will lead to a novel therapeutic strategy for ALS.
Watanabe S, Inami H, Oiwa K, Murata Y, Sakai S, Komine O, Sobue A, Iguchi Y, Katsuno M, Yamanaka K
"Aggresome formation and liquid–liquid phase separation independently induce cytoplasmic aggregation of TAR DNA-binding protein 43."
Cell Death Dis (2020) 11: 909. DOI: 10.1038/s41419-020-03116-2
The 43rd Annual Meeting of the Japan Neuroscience Society （7/29-8/1, Online Meeting）
・Prof. Yamanaka co-organized the symposium: "Infrastructures of the brain that support logistics solutions in health and disease" with Dr. Yu Hayashi (WPI-IIIS, Tsukuba Univ.).
・Drs. Komine, Sobue, and Watanabe gave oral/poster presentations.
61st Annual Meeting of the Japanese Society of Neurology （8/31-9/2, Okayama Convention Center and Online Meeting）
・Prof. Yamanaka gave an presentation in the symposium.
・Dr. Oiwa gave an presentation.
The 63rd Annual Meeting of the Japanese Society for Neurochemistry （9/10-9/12, Online Meeting）
・Prof. Yamanaka co-organized the symposium with Dr. Minako Ito (Kyusyu Univ.) and gave an presentation as a symposiast.
The 93rd Annual Meeting of the Japanese Biochemical Society （9/14-9/16, Online Meeting）
・Prof. Yamanaka co-organized the symposium: "Brain Infrastructure: A new logistic system of the brain in health and disease." with Dr. Kaoru Yamada (Univ. Tokyo).
・Drs. Komine and Watanabe gave presentations as symposiasts.
The 32nd Annual Meeting of the Japanese Society for Neurochemistry （10/1-10/2, Online Meeting）
・Prof. Yamanaka co-chaired the symposium: "microglia: frontiers in clinical and basic research" with Dr. Hideyuki Takeuchi (Yokohama City Univ.) and gave an presentation.
Konishi H., Okamoto T., Hara Y., Komine O., Tamada H., Maeda M., Osako F., Kobayashi M., Nishiyama A., Kataoka Y., Takai T., Udagawa N., Jung S., Ozato K., Tamura T., Tsuda M., Yamanaka K., Ogi T., Sato K., Kiyama H.
"Astrocytic phagocytosis is a compensatory mechanism for microglial dysfunction."
EMBO J (2020) 22: e104464. DOI: 10.15252/embj.2020104464
A group of researchers from the Universities of Liverpool (UK) and Nagoya (Japan) have shown that a Selenium based drug-molecule called ebselen and a number of other novel compounds developed at Liverpool can change many of the toxic characteristics of a protein, superoxide dismutase (SOD1), which causes some cases of ALS, also known as motor neuron disease as well as Lou Gehrig’s disease.
Amporndanai K, Rogers M, Watanabe S, Yamanaka K, O’Neill P. M., Hasnain S. S.
"Novel Selenium-based compounds with therapeutic potential for SOD1-linked Amyotrophic Lateral Sclerosis."
EBioMed (2020) 59: 102980. DOI: 10.1016/j.ebiom.2020.102980
Sugiyama M, Banno R, Yaginuma H, Taki K, Mizoguchi A, Tsunekawa T, Onoue T, Takagi H, Ito Y, Iwama S, Goto M, Suga H, Komine O, Yamanaka K, Arima H.
"Hypothalamic glial cells isolated by MACS reveal that microglia and astrocytes induce hypothalamic inflammation via different processes under high-fat diet conditions."
Neurochem Int (2020) 136: 104733. DOI: 10.1016/j.neuint.2020.104733
Nakazawa Y, Hara Y, Oka Y, Komine O, van den Heuvel D, Guo C, Daigaku Y, Isono M, He Y, Shimada M, Kato K, Jia N, Hashimoto S, Kotani Y, Miyoshi Y, Tanaka M, Sobue A, Mitsutake N, Suganami T, Masuda A, Ohno K, Nakada S, Mashimo T, Yamanaka K, Luijsterburg MS, Ogi T
"Ubiquitination of DNA Damage-Stalled RNAPII Promotes Transcription-Coupled Repair."
Cell (2020) 180(6): 1228-1244.e24. DOI: 10.1016/j.cell.2020.02.010
Our Lab members in 2020.
TDP-43 is a key molecule in ALS pathology. Transgenic mice models of TDP-43 suffer from acute toxicity induced by excess amounts of TDP-43 proteins. Therefore, we established TDP-43(M337V) knock-in mice by genome editing using Cas9 (A). The knock-in mice showed RNA deregulation dependent on TDP-43 gain-of-function mechanism (B), similar to the previous studies (White et al. (2018) Nat Neurosci etc.), but no motor neuron degeneration was observed (C). These results suggest that additional conformational change of TDP-43 protein may be needed to develop TDP-43 pathology.
Watanabe S, Oiwa K, Murata Y, Komine O, Sobue A, Endo F, Takahashi E and Yamanaka K
"ALS-linked TDP-43M337V knock-in mice exhibit splicing deregulation without neurodegeneration."
Molecular Brain (2020) 13: 8. DOI: 10.1186/s13041-020-0550-4
・Dr. Sobue: 2019 Nov The 38th Annual Meeting of Japan Society for Dementia Research
・Prof. Yamanaka, Dr. Watanabe: 2019 Dec 30th International Symposium on ALS/MND (Perth, Australia)
2019 Oct / Welcome party at our lab.
We investigated the pathological role of TDP-43 N-terminal fragments, which is also accumulated in ALS patients as well as full-length TDP-43 and TDP-43 C-terminal fragments. We produced TDP-ΔC knock-in mice, expressing TDP-43 N-terminal fragments at the similar level of endogenous TDP-43 (left panel). This mice showed age-dependent motor dysfunction (right panel) with reduced C-boutons, large cholinergic synapses on motor neurons, and Notch1-Akt signaling pathway (middle panel, arrowheads indicate C-boutons). Our data uncovered a detrimental role of N-terminal TDP-43 fragments in ALS pathology in mice, associated with suppression of Akt surviving signal.
Nishino K, Watanabe S, Shijie J, Murata Y, Oiwa K, Komine O, Endo F, Tsuiji H, Abe M, Sakimura K, Mishra A, Yamanaka K
"Mice deficient in the C-terminal domain of TAR DNA-binding protein 43 develop age-dependent motor dysfunction associated with impaired Notch1-Akt signaling pathway."
Acta Neuropathologica Communications (2019) 7(1): 118. DOI: 10.1186/s40478-019-0776-5
Group photo of our current laboratory members (2019 Apr in Higashi-yama Campus, Nagoya University).
Group Photo at the welcome party.
At our laboratory. Dr. Watanabe, Ms. Kinoshita, Mr. Sugiyama, and Prof. Yamanaka from the left.
Prof. Yamanaka (left) and Mr. Inami (right) in the poster session floor.
We reported that innate immune TRIF pathway plays an important role in protecting a microenvironment surrounding motor neurons by eliminating aberrantly activated astrocytes.
Komine O, Yamashita H, Fujimori-Tonou N, Koike M, Jin S, Moriwaki Y, Endo F, Watanabe S, Uematsu S, Akira S, Uchiyama Y, Takahashi R, Misawa H, Yamanaka K
"Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes."
Cell Death & Differentiation in press doi:10.1038/s41418-018-0098-3.