Hitoshi Osuga
Tokai University
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Hitoshi Osuga.
Nature Genetics | 2001
Shinji Hadano; Collette K. Hand; Hitoshi Osuga; Yoshiko Yanagisawa; Asako Otomo; Rebecca S. Devon; Natsuki Miyamoto; Junko Showguchi-Miyata; Yoshinori Okada; Roshni R. Singaraja; Denise A. Figlewicz; Thomas J. Kwiatkowski; Betsy A. Hosler; Tally Sagie; Jennifer Skaug; Jamal Nasir; Robert H. Brown; Stephen W. Scherer; Guy A. Rouleau; Michael R. Hayden; Joh-E Ikeda
Amyotrophic lateral sclerosis 2 (ALS2) is an autosomal recessive form of juvenile ALS and has been mapped to human chromosome 2q33. Here we report the identification of two independent deletion mutations linked to ALS2 in the coding exons of the new gene ALS2. These deletion mutations result in frameshifts that generate premature stop codons. ALS2 is expressed in various tissues and cells, including neurons throughout the brain and spinal cord, and encodes a protein containing multiple domains that have homology to RanGEF as well as RhoGEF. Deletion mutations are predicted to cause a loss of protein function, providing strong evidence that ALS2 is the causative gene underlying this form of ALS.
Journal of Cerebral Blood Flow and Metabolism | 2002
Fuhu Wang; Dale Corbett; Hitoshi Osuga; Sachiko Osuga; Joh-E Ikeda; Ruth S. Slack; Matthew J. Hogan; Antoine M. Hakim; David S. Park
Increasing evidence suggests that cyclin-dependent kinases participate in neuronal death induced by multiple stresses in vitro. However, their role in cell death paradigms in vivo is not well characterized. Accordingly, the authors examined whether cyclin-dependent kinase inhibition resulted in functionally relevant and sustained neuroprotection in a model of global ischemia. Intracerebroventricular administration of the cyclin-dependent kinase inhibitor flavopiridol, immediately or at 4 hours postreperfusion after a global insult, reduced injury in the CA1 of the hippocampus when examined 7 days after reperfusion. No significant protection was observed when flavopiridol was administered 8 hours after reperfusion. The tumor-suppressor retinoblastoma protein, a substrate of cyclin-dependent kinase, was phosphorylated on a cyclin-dependent kinase consensus site after the global insult; this phosphorylation was inhibited by flavopiridol administration. Importantly, flavopiridol had no effect on core body temperature, suggesting that the mechanism of neuroprotection was through cyclin-dependent kinase inhibition but not through hypothermia. Furthermore, inhibition of cyclin-dependent kinases improved spatial learning behavior as assessed by the Morris water maze 7 to 9 days after reperfusion. However, the histologic protection observed at day 7 was absent 28 days after reperfusion. These results indicate that cyclin-dependent kinase inhibition provides an extended period of morphologic and functional neuroprotection that may allow time for other neuroprotective modalities to be introduced.
Experimental Neurology | 2008
Kazunori Tanaka; Yoshinori Okada; Takuya Kanno; Asako Otomo; Yoshiko Yanagisawa; Junko Shouguchi-Miyata; Etsuko Suga; Eri Kohiki; Kyuichiro Onoe; Hitoshi Osuga; Masashi Aoki; Shinji Hadano; Yasuto Itoyama; Joh-E Ikeda
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a selective loss of motor neurons in the motor cortex, brainstem, and spinal cord. It has been shown that oxidative stress plays a pivotal role in the progression of this motor neuron loss. We have previously reported that L-745,870, a dopamine D4 receptor antagonist, selectively inhibits oxidative stress-induced cell death in vitro and exerts a potent neuroprotective effect against ischemia-induced neural cell damage in gerbil. To investigate the efficacy of L-745,870 in the treatment of ALS, we here conducted a chronic administration of L-745,870 to transgenic mice expressing a mutated form of human superoxide dismutase gene (SOD1(H46R)); a mouse model of familial ALS, and assessed whether the mice benefit from this treatment. The pre-onset administration of L-745,870 significantly delayed the onset of motor deficits, slowed the disease progression, and extended a life span in transgenic mice. These animals showed a delayed loss of anterior horn cells in the spinal cord concomitant with a reduced level of microglial activation at a late symptomatic stage. Further, the post-onset administration of L-745,870 to the SOD1(H46R) transgenic mice remarkably slowed the disease progression and extended their life spans. Taken together, our findings in a rodent model of ALS may have implication that L-745,870 is a possible novel therapeutic means to the treatment of ALS.
Journal of Cerebral Blood Flow and Metabolism | 2005
Yoshinori Okada; Harumi Sakai; Eri Kohiki; Etsuko Suga; Yoshiko Yanagisawa; Kazunori Tanaka; Shinji Hadano; Hitoshi Osuga; Joh-E Ikeda
Neuronal apoptosis inhibitory protein (NAIP/BIRC1), the inhibitor of apoptosis protein (IAP) family member, suppresses neuronal cell death induced by a variety of insults, including cell death from ischemia and stroke. The goal of the present study was to develop an efficient method for identification of compounds with the ability to upregulate endogenous NAIP and to determine the effects on these compounds on the cellular response to ischemia. A novel NAIP-enzyme-linked immunosorbent assay (ELISA)-based in vitro drug-screening system is established. Use of this system identified an antagonist of dopamine D4 receptor, termed L-745,870, with a potent NAIP upregulatory effect. L-745,870-mediated NAIP upregulation in neuronal and nonneuronal cultured cells resulted in decreased vulnerability to oxidative stress-induced apoptosis. Reducing NAIP expression via RNA interference techniques resulted in prevention of L-745,870-mediated protection from oxidative stress. Further, systemic administration of L-745,870 attenuated ischemia-induced damage of the hippocampal CA1 neurons and upregulated NAIP expression in the rescued hippocampal CA1 neurons in a gerbil model. These data suggest that the NAIP upregulating compound, L-745,870, has therapeutic potential in acute ischemic disorders and that our NAIP-ELISA-based drug screening may facilitate the discovery of novel neuroprotective compounds.
Biochemical and Biophysical Research Communications | 2008
Asako Otomo; Ryota Kunita; Kyoko Suzuki-Utsunomiya; Hikaru Mizumura; Kyuichiro Onoe; Hitoshi Osuga; Shinji Hadano; Joh-E Ikeda
Loss of function mutations in the ALS2 gene account for a number of juvenile/infantile recessive motor neuron diseases, indicating that its gene product, ALS2/alsin, plays a crucial role in maintenance and survival for a subset of neurons. ALS2 acts as a guanine nucleotide exchange factor (GEF) for the small GTPase Rab5 and is implicated in endosome dynamics in cells. However, the role of ALS2 in neurons remains unclear. To elucidate the neuronal ALS2 functions, we investigate cellular phenotypes of ALS2-deficient primary cultured neurons derived from Als2-knockout (KO) mice. Here, we show that ALS2 deficiency results not only in the delay of axon outgrowth in hippocampal neurons, but also in a decreased level of the fluid phase horseradish peroxidase (HRP) uptake, which represents the activity for macropinocytic endocytosis, in cortical neurons. Thus, ALS2 may act as a modulator in neuronal differentiation and/or development through regulation of membrane dynamics.
Proceedings of the National Academy of Sciences of the United States of America | 2000
Hitoshi Osuga; Sachiko Osuga; Fuhu Wang; Raouf Fetni; Matthew J. Hogan; Ruth S. Slack; Antoine M. Hakim; Joh-E Ikeda; David S. Park
Human Molecular Genetics | 2003
Asako Otomo; Shinji Hadano; Takeya Okada; Hikaru Mizumura; Ryota Kunita; Hitoshi Nishijima; Junko Showguchi-Miyata; Yoshiko Yanagisawa; Eri Kohiki; Etsuko Suga; Masanori Yasuda; Hitoshi Osuga; Takeharu Nishimoto; Shuh Narumiya; Joh-E Ikeda
Genomics | 2000
Noriko Matsuyama; Shinji Hadano; Kyuichiro Onoe; Hitoshi Osuga; Junko Showguchi-Miyata; Yoichi Gondo; Joh-E Ikeda
Biochemical and Biophysical Research Communications | 2007
Kyoko Suzuki-Utsunomiya; Shinji Hadano; Asako Otomo; Ryota Kunita; Hikaru Mizumura; Hitoshi Osuga; Joh-E Ikeda
Archive | 2003
Joh-E Ikeda; Yoshinori Okada; Harumi Sakai; Hitoshi Osuga