Updated on 2024/12/14

写真a

 
SASAJIMA Hitoshi
 
Organization
Center Research technology support center
External link

Degree

  • 博士（薬学） ( 2004.3   北海道大学 )

Research Interests

  • dopamine

  • HDAC

  • Optogenetics

  • MAO

  • neurodegeneration

Research Areas

  • Life Science / Cell biology

  • Life Science / Pharmaceutical hygiene and biochemistry

  • Life Science / Physiology  / Neurodegeneration

Education

  • Grad School of Hokkaido Univ   Dept of Parmaceutical Science

    2001.4 - 2004.3

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  • Hokkaido University   Graduate School, Division of Pharmaceutical Sciences

    - 2004.3

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    Country： Japan

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  • Hokkaido University   Faculty of Pharmaceutical Science

    - 1999.3

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    Country： Japan

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Professional Memberships

  • The molecular biology society of japan

    2018.10

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  • Japan Society for Cell Biology

    2018.4

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Papers

  • Interaction between PI3K and the VDAC2 channel tethers Ras-PI3K-positive endosomes to mitochondria and promotes endosome maturation. International journal

    Aya O Satoh, Yoichiro Fujioka, Sayaka Kashiwagi, Aiko Yoshida, Mari Fujioka, Hitoshi Sasajima, Asuka Nanbo, Maho Amano, Yusuke Ohba

    Cell reports   42 ( 3 )   112229 - 112229   2023.3

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    Language：English   Publishing type：Research paper (scientific journal)  

    Intracellular organelles of mammalian cells communicate with one another during various cellular processes. The functions and molecular mechanisms of such interorganelle association remain largely unclear, however. We here identify voltage-dependent anion channel 2 (VDAC2), a mitochondrial outer membrane protein, as a binding partner of phosphoinositide 3-kinase (PI3K), a regulator of clathrin-independent endocytosis downstream of the small GTPase Ras. VDAC2 tethers endosomes positive for the Ras-PI3K complex to mitochondria in response to cell stimulation with epidermal growth factor and promotes clathrin-independent endocytosis, as well as endosome maturation at membrane association sites. With an optogenetics system to induce mitochondrion-endosome association, we find that, in addition to its structural role in such association, VDAC2 is functionally implicated in the promotion of endosome maturation. The mitochondrion-endosome association thus plays a role in the regulation of clathrin-independent endocytosis and endosome maturation.

    DOI： 10.1016/j.celrep.2023.112229

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  • Folding Latency of Fluorescent Proteins Affects the Mitochondrial Localization of Fusion Proteins. Reviewed

    Sayaka Kashiwagi, Yoichiro Fujioka, Aya O Satoh, Aiko Yoshida, Mari Fujioka, Prabha Nepal, Atsushi Tsuzuki, Ozora Aoki, Sarad Paudel, Hitoshi Sasajima, Yusuke Ohba

    Cell structure and function   44 ( 2 )   183 - 194   2019.12

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    Language：English   Publishing type：Research paper (scientific journal)  

    The discovery of fluorescent proteins (FPs) has revolutionized cell biology. The fusion of targeting sequences to FPs enables the investigation of cellular organelles and their dynamics; however, occasionally, such fluorescent fusion proteins (FFPs) exhibit behavior different from that of the native proteins. Here, we constructed a color pallet comprising different organelle markers and found that FFPs targeted to the mitochondria were mislocalized when fused to certain types of FPs. Such FPs included several variants of Aequorea victoria green FP (avGFP) and a monomeric variant of the red FP. Because the FFPs that are mislocalized include FPs with faster maturing or folding mutations, the increase in the maturation rate is likely to prevent their expected localization. Indeed, when we reintroduced amino acid substitutions so that the FP sequences were equivalent to that of wild-type avGFP, FFP localization to the mitochondria was significantly enhanced. Moreover, similar amino acid substitutions improved the localization of mitochondria-targeted pHluorin, which is a pH-sensitive variant of GFP, and its capability to monitor pH changes in the mitochondrial matrix. Our findings demonstrate the importance of selecting FPs that maximize FFP function.Key words: fluorescent protein, organelle, fusion protein, mitochondria.

    DOI： 10.1247/csf.19028

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  • Localization of BCR-ABL to Stress Granules Contributes to Its Oncogenic Function. Reviewed

    Sayaka Kashiwagi, Yoichiro Fujioka, Takeshi Kondo, Aya O Satoh, Aiko Yoshida, Mari Fujioka, Hitoshi Sasajima, Maho Amano, Takanori Teshima, Yusuke Ohba

    Cell structure and function   44 ( 2 )   195 - 204   2019.12

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    The oncogenic tyrosine kinase BCR-ABL activates a variety of signaling pathways and plays a causative role in the pathogenesis of chronic myelogenous leukemia (CML); however, the subcellular distribution of this chimeric protein remains controversial. Here, we report that BCR-ABL is localized to stress granules and that its granular localization contributes to BCR-ABL-dependent leukemogenesis. BCR-ABL-positive granules were not colocalized with any markers for membrane-bound organelles but were colocalized with HSP90a, a component of RNA granules. The number of such granules increased with thapsigargin treatment, confirming that the granules were stress granules. Given that treatment with the ABL kinase inhibitor imatinib and elimination of the N-terminal region of BCR-ABL abolished granule formation, kinase activity and the coiled-coil domain are required for granule formation. Whereas wild-type BCR-ABL rescued the growth defect in IL-3-depleted Ba/F3 cells, mutant BCR-ABL lacking the N-terminal region failed to do so. Moreover, forced tetramerization of the N-terminus-deleted mutant could not restore the growth defect, indicating that granule formation, but not tetramerization, through its N-terminus is critical for BCR-ABL-dependent oncogenicity. Our findings together provide new insights into the pathogenesis of CML by BCR-ABL and open a window for developing novel therapeutic strategies for this disease.Key words: BCR-ABL, subcellular localization, stress granule.

    DOI： 10.1247/csf.19033

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  • Etizolam attenuates the reduction in cutaneous temperature induced in mice by exposure to synthetic predator odor. Reviewed International journal

    Sadaharu Miyazono, Kaede Hasegawa, Seri Miyazaki, Hikari Sakakima, Shun Konno, Saori Meguro, Hitoshi Sasajima, Tomohiro Noguchi, Kazumi Osada, Makoto Kashiwayanagi

    European journal of pharmacology   824   157 - 162   2018.4

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    Anxiety- and stress-related disorders can be debilitating psychiatric conditions in humans. To prevent or ameliorate these conditions, reliable animal models are needed to evaluate the effects of anxiolytic drugs. Previously, we found that a mixture of three pyrazine analogues (P-mix) that were present at high levels in wolf urine induced fear-related responses in mice, rats and deer. A change in cutaneous temperature was shown to be induced by acute stress simultaneously with changes in heart rate, arterial pressure and freezing behavior, raising the possibility that cutaneous temperature could be used as an index of stress. In the present study, using infrared thermography, we showed that exposure of mice to P-mix induced a decrease in cutaneous temperature. We then examined the dose-dependent effects of an anxiolytic drug, etizolam (0-20 mg/kg), on the temperature decrease. Pre-administration of etizolam (5 mg/kg or higher) inhibited the P-mix-induced decrease in cutaneous temperature. Exposure to P-mix induced Fos-immunoreactivity, a marker of neuronal excitation, at the mouse amygdala and hypothalamus, and etizolam (5 mg/kg) attenuated that immunoreactivity. The present results suggested that the measurement of cutaneous P-mix-induced temperature changes in mice could be used as an animal model for evaluating the effects of anxiolytic drugs.

    DOI： 10.1016/j.ejphar.2018.02.015

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  • Intranasal Administration of Rotenone to Mice Induces Dopaminergic Neurite Degeneration of Dopaminergic Neurons in the Substantia Nigra. Reviewed

    Hitoshi Sasajima, Sadaharu Miyazono, Tomohiro Noguchi, Makoto Kashiwayanagi

    Biological & pharmaceutical bulletin   40 ( 1 )   108 - 112   2017

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    Language：English   Publishing type：Research paper (scientific journal)  

    Exposure to environmental neurotoxins is suspected to be a risk factor for sporadic progressive neurodegenerative diseases. Parkinson's disease has been associated with exposure to the pesticide rotenone, a mitochondrial respiration inhibitor. We previously reported that intranasal administration of rotenone in mice induced dopaminergic (DA) neurodegeneration in the olfactory bulb (OB) and reduced olfactory functions. In the present study, we investigated the DA neurons in the brains of mice that were administered rotenone intranasally for an extended period. We found that the olfactory function of mice was attenuated by rotenone administration. Electrophysiological analysis of the mitral cells, which are output neurons in the OB, revealed that the inhibitory input into the mitral cells was retarded. In the immunohistochemical analysis, neurite degeneration of DA neurons in the substantia nigra was observed in rotenone-administered mice, indicating that rotenone progressively initiated the degeneration of cerebral DA neurons via the nasal route.

    DOI： 10.1248/bpb.b16-00654

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  • Parallel Processing by Two Olfactory Systems

    NOGUCHI Tomohiro, SASAJIMA Hitoshi, MIYAZONO Sadaharu, KASHIWAYANAGI Makoto

    Seibutsu Butsuri   57 ( 1 )   23 - 25   2017

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    Language：Japanese   Publisher：The Biophysical Society of Japan General Incorporated Association  

    DOI： 10.2142/biophys.57.023

    CiNii Books

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  • Intranasal administration of rotenone in mice attenuated olfactory functions through the lesion of dopaminergic neurons in the olfactory bulb. Reviewed International journal

    Hitoshi Sasajima, Sadaharu Miyazono, Tomohiro Noguchi, Makoto Kashiwayanagi

    Neurotoxicology   51   106 - 15   2015.12

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    Many environmental chemicals are thought to affect brain function. It was reported that chemicals in the nasal cavity directly reach the brain through the connection between olfactory neurons and the olfactory bulb (OB). In this 'olfactory transport,' xenobiotics absorbed at the nasal mucosa reach the brain by bypassing some physical barriers and defenses, and thus olfactory transport is suspected to be a vulnerable mechanism of the brain against invasion threats of environmental chemicals. In this study, we focused on the neuronal toxicity of rotenone administered intranasally to mice. The results showed that the mice that were administered rotenone had attenuated olfactory functions. We also found that intranasally administered rotenone induced acute mitochondrial stress at the OB. The repeated administration of rotenone resulted in a decrease in the number of dopaminergic neurons, which are inhibitory interneurons in the OB. Taken together, our findings suggest that the inhalation of environmental toxins induces the neurodegeneration of cranial neurons through olfactory transport, and that olfactory dysfunction may be induced as an earliest symptom of neurodegeneration caused by inhaled neurotoxins.

    DOI： 10.1016/j.neuro.2015.10.006

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  • Similar rate of information transfer on stimulus intensity in accessory and main olfactory bulb output neurons. Reviewed International journal

    Tomohiro Noguchi, Hitoshi Sasajima, Sadaharu Miyazono, Makoto Kashiwayanagi

    Neuroscience letters   576   56 - 61   2014.7

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    Recently, evidence has accumulated that the vomeronasal system cooperates with the main olfactory system to process volatile cues that regulate the animal's behavior. This is contradictory to the traditional view that the vomeronasal system is quite different from the main olfactory system in the time scale of information processing. Particularly, the firing rate of mitral/tufted cells in the accessory olfactory bulb (MTAOB) is known to be significantly lower than that of mitral cells in the main olfactory bulb (MCMOB). To address this question of whether the low-frequency firing in MTAOB carries less information than the high-frequency firing in MCMOB in the early stages of stimulation, we compared MTAOB and MCMOB for their firing mechanisms and information transfer characteristics. A model computation demonstrated that the inherent channel kinetics of MTAOB was responsible for their firing at a lower frequency than MCMOB. Nevertheless, our analysis suggested that MTAOB were comparable to MCMOB in both the amount and speed of information transfer about depolarizing current intensity immediately after current injection onset (<200ms). Our results support a hypothesis of simultaneous processing of common cues in both systems.

    DOI： 10.1016/j.neulet.2014.05.058

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  • Hard-diet feeding recovers neurogenesis in the subventricular zone and olfactory functions of mice impaired by soft-diet feeding. Reviewed International journal

    Chizuru Utsugi, Sadaharu Miyazono, Kazumi Osada, Hitoshi Sasajima, Tomohiro Noguchi, Mitsuyoshi Matsuda, Makoto Kashiwayanagi

    PloS one   9 ( 5 )   e97309   2014

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    Language：English   Publishing type：Research paper (scientific journal)  

    The subventricular zone (SVZ) generates an immense number of neurons even during adulthood. These neurons migrate to the olfactory bulb (OB) and differentiate into granule cells and periglomerular cells. The information broadcast by general odorants is received by the olfactory sensory neurons and transmitted to the OB. Recent studies have shown that a reduction of mastication impairs both neurogenesis in the hippocampus and brain functions. To examine these effects, we first measured the difference in Fos-immunoreactivity (Fos-ir) at the principal sensory trigeminal nucleus (Pr5), which receives intraoral touch information via the trigeminal nerve, when female adult mice ingested a hard or soft diet to explore whether soft-diet feeding could mimic impaired mastication. Ingestion of a hard diet induced greater expression of Fos-ir cells at the Pr5 than did a soft diet or no diet. Bromodeoxyuridine-immunoreactive (BrdU-ir) structures in sagittal sections of the SVZ and in the OB of mice fed a soft or hard diet were studied to explore the effects of changes in mastication on newly generated neurons. After 1 month, the density of BrdU-ir cells in the SVZ and OB was lower in the soft-diet-fed mice than in the hard-diet-fed mice. The odor preferences of individual female mice to butyric acid were tested in a Y-maze apparatus. Avoidance of butyric acid was reduced by the soft-diet feeding. We then explored the effects of the hard-diet feeding on olfactory functions and neurogenesis in the SVZ of mice impaired by soft-diet feeding. At 3 months of hard-diet feeding, avoidance of butyric acid was reversed and responses to odors and neurogenesis were recovered in the SVZ. The present results suggest that feeding with a hard diet improves neurogenesis in the SVZ, which in turn enhances olfactory function at the OB.

    DOI： 10.1371/journal.pone.0097309

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  • Polyubiquitination of the B-cell translocation gene 1 and 2 proteins is promoted by the SCF ubiquitin ligase complex containing βTrCP. Reviewed

    Hitoshi Sasajima, Koji Nakagawa, Makoto Kashiwayanagi, Hideyoshi Yokosawa

    Biological & pharmaceutical bulletin   35 ( 9 )   1539 - 45   2012

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    B-cell translocation gene 1 and 2 (BTG1 and BTG2) are members of the BTG/Tob antiproliferative protein family, which is able to regulate the cell cycle and cell proliferation. We previously reported that BTG1, BTG2, Tob, and Tob2 are degraded via the ubiquitin-proteasome pathway. In this study, we investigated the mechanism of polyubiquitination of BTG1 and BTG2. Since the Skp1-Cdc53/Cullin 1-F-box protein (SCF) complex functions as one of the major ubiquitin ligases for cell cycle regulation, we first examined interactions between BTG proteins and components of the SCF complex, and found that BTG1 and BTG2 were capable of interacting with the SCF complex containing Cullin-1 (a scaffold protein) and Skp1 (a linker protein). As the SCF complex can ubiquitinate various target proteins by substituting different F-box proteins as subunits that recognize different target proteins, we next examined which F-box proteins could bind the two BTG proteins, and found that Skp2, β-transducin repeat-containing protein 1 (βTrCP1), and βTrCP2 were able to associate with both BTG1 and BTG2. Furthermore, we obtained evidence showing that βTrCP1 enhanced the polyubiquitination of both BTG1 and BTG2 more efficiently than Skp2 did, and that an F-box truncated mutant of βTrCP1 had a dominant negative effect on this polyubiquitination. Thus, we propose that BTG1 and BTG2 are subjected to polyubiquitination, more efficiently when it is mediated by SCFβTrCP than by SCFSkp2.

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  • Epidemiology of Epstein-Barr virus, cytomegalovirus, and Kaposi's sarcoma-associated herpesvirus infections in peripheral blood leukocytes revealed by a multiplex PCR assay. Reviewed International journal

    Morie Nishiwaki, Masahiro Fujimuro, Yasuhiro Teishikata, Hisanori Inoue, Hitoshi Sasajima, Kazuhiro Nakaso, Kenji Nakashima, Hidetaka Sadanari, Tomohiro Yamamoto, Yoshie Fujiwara, Naoki Ogawa, Hideyoshi Yokosawa

    Journal of medical virology   78 ( 12 )   1635 - 42   2006.12

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    A multiplex polymerase chain reaction (PCR) has been developed for the simultaneous detection of Epstein-Barr virus (EBV), cytomegalovirus (CMV), and Kaposi's sarcoma-associated herpesvirus (KSHV) in a clinical sample. Primers of multiplex PCR were designed to amplify specific regions of the EBV EBNA1, CMV IE2, and KSHV LANA genes. This multiplex PCR assay was found to have detection sensitivities of 1-10 copies of purified viral DNA cloned into the plasmid. To assess diagnostic and pre-clinical applications with this method, we utilized KSHV-positive primary effusion lymphoma (PEL) cells, EBV-positive Burkitt's lymphoma cells, CMV-infected fibroblast cells, and clinically prepared peripheral blood leukocytes (PBLs) that had been infected with viruses. We found that this multiplex PCR assay has high sensitivity and specificity for simultaneous detection of EBV, CMV, and KSHV genomes in a single amplification from a clinical material. Using this multiplex PCR assay, we investigated the prevalence of EBV, CMV, and KSHV in PBL samples from normal Japanese randomly selected. KSHV, EBV, and CMV genomes were detected in samples from 2 (0.2%), 377 (39.5%), and 27 (2.8%) of the 953 blood donors, respectively. Interestingly, both EBV and CMV genomes were detected in samples from all KSHV-positive donors.

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  • Link between the ubiquitin conjugation system and the ISG15 conjugation system: ISG15 conjugation to the UbcH6 ubiquitin E2 enzyme. Reviewed International journal

    Tomoharu Takeuchi, Sachiko Iwahara, Yasushi Saeki, Hitoshi Sasajima, Hideyoshi Yokosawa

    Journal of biochemistry   138 ( 6 )   711 - 9   2005.12

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    ISG15 is a ubiquitin-like protein that is upregulated on treatment with interferon. ISG15 is considered to be covalently conjugated to cellular proteins through a sequential reaction similar to that of the ubiquitin conjugation system consisting of E1/E2/E3 enzymes: UBE1L and UbcH8 have been reported to function as E1 and E2 enzymes, respectively, for ISG15 conjugation. Several cellular proteins have been identified as targets for ISG15 conjugation, but the roles of ISG15 conjugation remain unclear. In this study, we found that UbcH6 and UbcH8, E2 enzymes for ubiquitin conjugation, are covalently modified by ISG15. We also found that UbcH6 is capable of forming a thioester intermediate with ISG15 through Cys131. We determined that the Lys136 residue near the catalytic site Cys131 is the ISG15 conjugation site in UbcH6. We isolated ISG15-modified and unmodified UbcH6 proteins, and analyzed their abilities to form thioester intermediates with ubiquitin. A ubiquitin thioester intermediate was detected in the case of unmodified UbcH6, but not in that of ISG15-modified UbcH6, strongly suggesting that ISG15 conjugation to UbcH6 suppresses its ubiquitin E2 enzyme activity. Thus, we provide evidence for a link between the ubiquitin conjugation system and the ISG15 conjugation system.

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  • Antiproliferative proteins of the BTG/Tob family are degraded by the ubiquitin-proteasome system. Reviewed International journal

    Hitoshi Sasajima, Koji Nakagawa, Hideyoshi Yokosawa

    European journal of biochemistry   269 ( 14 )   3596 - 604   2002.7

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    BTG/Tob family proteins, which are characterized by similarities in their N-terminal BTG/Tob homology domains, control cell growth negatively. Among the BTG/Tob family members, BTG2/TIS21/PC3 proteins have been reported to have short lives and to be degraded by the proteasome. However, the mechanisms regulating the stabilities of other BTG/Tob family proteins have not yet been clarified. Here, we report that BTG1, Tob, and Tob2 proteins, as well as BTG2 protein, are degraded by the ubiquitin-proteasome system; the degradation of Tob protein in HeLa cells and the degradation of BTG1, BTG2, Tob and Tob2 proteins transiently expressed in HEK293 cells were inhibited by treatments with proteasome-specific inhibitors. Co-expression of BTG1, BTG2, Tob, or Tob2 protein with ubiquitin in HEK293 cells revealed specific multiubiquitination of each of the four proteins. Although the full-length and N-terminal truncated forms of BTG1, BTG2, Tob, and Tob2 proteins were unstable, the respective C-terminal truncated forms were found to be almost stable, suggesting that the C-terminal regions control the stabilities of BTG1, BTG2, Tob, and Tob2 proteins. In addition, it was found that the respective C-terminal regions confer instability on green fluorescent protein, a normally stable protein. Thus, it can be concluded that the C-terminal regions are necessary and sufficient to control the stabilities of BTG1, BTG2, Tob, and Tob2 proteins.

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  • Assembly of the 26S proteasome is regulated by phosphorylation of the p45/Rpt6 ATPase subunit. Reviewed International journal

    K Satoh, H Sasajima, K I Nyoumura, H Yokosawa, H Sawada

    Biochemistry   40 ( 2 )   314 - 9   2001.1

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    We investigated whether the assembly/disassembly of the 26S proteasome is regulated by phosphorylation/dephosphorylation. The regulatory complex disassembled from the 26S proteasome was capable of phosphorylating the p45/Sug1/Rpt6 subunit, suggesting that the protein kinase is activated upon dissociation of the 26S proteasome or that the phosphorylation site of p45 becomes susceptible to the protein kinase. In addition, the p45-phosphorylated regulatory complex was found to be incorporated into the 26S proteasome. When the 26S proteasome was treated with alkaline phosphatase, it was dissociated into the 20S proteasome and the regulatory complex. Furthermore, the p45 subunit and the C3/alpha2 subunit were cross-linked with DTBP, whereas these subunits were not cross-linked by dephosphorylating the 26S proteasome. These results indicate that the 26S proteasome is disassembled into the constituent subcomplexes by dephosphorylation and that it is assembled by phosphorylation of p45 by a protein kinase, which is tightly associated with the regulatory complex. It was also revealed that the p45 subunit is directly associated with the 20S proteasome alpha-subunit C3 in a phosphorylation-dependent manner.

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MISC

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Presentations

  • 経鼻投与を用いた嗅覚機能におけるGABAの役割の検討

    堀内至, 宮園貞治, 笹島仁, 野口智弘, 柏柳誠

    第26回 北海道薬物作用談話会 

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    Event date： 2012.7

    Language：Japanese   Presentation type：Oral presentation (general)  

    Venue：札幌  

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  • Experience-dependent plasticity in the accessory olfactory bulb

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    Event date： 2011.9

    Language：Japanese   Presentation type：Symposium, workshop panel (public)  

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  • KSHV由来LANAタンパク質の新規C末端プロセシング体とがん化における役割

    笹島仁, 中村哲也, 横沢英良, 藤室雅弘

    日本分子生物学会 第27回年会 

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    Event date： 2004.12

    Language：Japanese   Presentation type：Poster presentation  

    Venue：神戸  

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  • プロテオーム解析によるカポジ肉腫関連ヘルペスウイルス核抗原（LANA）結合タンパク質の探索

    笹島仁, 中村哲也, 横沢英良, 藤室雅弘

    日本ウイルス学会 第52回学術集会・総会 

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    Event date： 2004.11

    Language：Japanese   Presentation type：Poster presentation  

    Venue：横浜  

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  • SCF-betaTrCPユビキチンリガーゼによる細胞増殖抑制因子BTG1とBTG2のポリユビキチン化

    笹島仁, 中川宏治, 横沢英良

    日本生化学会 第77回大会 

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    Event date： 2004.10

    Language：Japanese   Presentation type：Poster presentation  

    Venue：横浜  

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  • 細胞増殖抑制因子Tob/BTGファミリーのユビキチン依存的分解機構に関する研究 -BTGタンパク質の分解に関わるSCF複合体-

    笹島仁, 中川宏治, 横沢英良

    日本薬学会 第123回年会 

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    Event date： 2003.3

    Language：Japanese   Presentation type：Poster presentation  

    Venue：長崎  

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  • 細胞増殖抑制因子Tob/BTGファミリータンパク質の分解機構

    笹島仁, 中川宏治, 横沢英良

    日本分子生物学会 第24回年会 

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    Event date： 2001.12

    Language：Japanese   Presentation type：Poster presentation  

    Venue：横浜  

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Research Projects

  • 中枢性嗅覚障害における嗅球ドパミン神経細胞死と匂い嗅ぎ呼吸調節の因果関係

    Grant number：23K08904  2023.4 - 2026.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    野口 智弘, 志賀 英明, 佐藤 元, 笹島 仁, 宮園 貞治

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    Grant amount：\4,680,000 （ Direct Cost: \3,600,000 、 Indirect Cost：\1,080,000 ）

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  • A study for therapeutic approach of dopaminergic neurodegeneration through ferroptosis

    Grant number：22K11848  2022.4 - 2026.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant amount：\4,160,000 （ Direct Cost: \3,200,000 、 Indirect Cost：\960,000 ）

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  • The ameliorating effect of rosmarinic acid on mitochondrial stress-induced dopaminergic cell death.

    2021.10 - 2022.9

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  • Spatiotemporal control of synapse formation on dopaminergic interneurons in mouse olfactory bulbs during recovery from olfactory impairments.

    Grant number：20K09683  2020.4 - 2023.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

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    Grant amount：\4,030,000 （ Direct Cost: \3,100,000 、 Indirect Cost：\930,000 ）

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  • ドパミン代謝とミトコンドリアストレスによる細胞毒性の相互増強機構

    Grant number：17K08302  2017.4 - 2020.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    笹島 仁

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    Grant amount：\4,680,000 （ Direct Cost: \3,600,000 、 Indirect Cost：\1,080,000 ）

    黒質緻密部ドパミン神経細胞の変性・脱落は、進行性中枢神経変性疾患であるパーキンソン病の責任病変とされる。しかし、孤発性パーキンソン病の発症に至るメカニズムは現在まで不明である。これまでに明らかとなった家族性パーキンソン病の責任遺伝子や、薬剤性パーキンソン病モデル動物は、ミトコンドリアの品質管理機構の破綻やミトコンドリア呼吸鎖機能の異常がドパミン細胞死を加速させることを示唆している。一方、ドパミンはその分解代謝過程において、活性酸素や毒性代謝物を生じることが報告されている。そのため、ミトコンドリアストレスとドパミン代謝機構が相互作用することでドパミン神経細胞に特異的な脆弱性がもたらされると予見されるが、両者の関連機序は依然として不明である。
    本研究では、ゲノム編集により樹立したドパミン代謝遺伝子ノックアウト細胞を用いて、ドパミン代謝機構とミトコンドリアストレスによる細胞毒性の増強機構を検証し、薬理的なドパミン代謝調節およびミトコンドリア機能調節による神経変性の阻止方法を探索、評価する。これまで、神経成長因子によりドパミン神経細胞様に分化したラットPC12細胞において、ミトコンドリア呼吸鎖阻害剤であるロテノンがもたらす細胞死がドパミン産生に依存すること、特定のドパミン分解代謝酵素の阻害がロテノンによる細胞死を抑制すること、カテコール骨格を有するハーブ由来抗酸化成分も同様にこの細胞死を抑制することを見出した。これらは、予防医学としてのドパミン神経変性阻止の可能性を示唆するものである。さらに、分化PC12細胞に対してロテノンが誘導する細胞死が、非アポトーシス性の細胞死であることを見出した。現在。ミトコンドリアストレスとドパミン代謝の介在による神経細胞死誘導機構について詳細を検討中である。

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  • Elucidation of neural and molecular mechanisms regulating brain function by oral sensation

    Grant number：15K07962  2015.4 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Kashiwayanagi Makoto

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    Grant amount：\4,810,000 （ Direct Cost: \3,700,000 、 Indirect Cost：\1,110,000 ）

    In this study, the neural pathway where oral sensory information is transmitted to the substantia nigra parenchyma were investigated when mouse ingested chow. For example, neurons at the cerebral cortex somatosensory area, lateral reticular body, pontine nucleus, trigeminal spinal cord tract were excited. In addition, at the olfactory bulb where nerve cells newly generated in the subventricular zone migrated, the activity of interneurons such as the change of GABA release was affected. These results directly indicate that the decrease in migration of newly generated cells to the olfactory bulb associated with the decrease in neurogenesis in the subventricular zone of mice fed a powder diet affects the mitral cell, output cells of the olfactory bulb, activity.

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  • The vulnerability of dopaminergic neurons via olfactory transport pathway

    Grant number：26860053  2014.4 - 2018.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    SASAJIMA Hitoshi

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    Grant amount：\3,380,000 （ Direct Cost: \2,600,000 、 Indirect Cost：\780,000 ）

    In Parkinson's disease, most of patients suffer dysosmia prior to motor symptoms. However, the etiology of this dysosmia has not been fully understood yet. Via the olfactory transport pathway, environmental chemicals can directly reach to the brain. Therefore the olfactory transport is concerned as one of vulnerable pathways for brain against environmental toxins. In this study, we investigated dopaminergic neurodegeneration that mediated by olfactory transport of neurotoxin. Intranasally administered rotenone induced dopaminergic neurodegeneration in the olfactory bulb of mice. Indeed, olfactory functions were attenuated by rotenone. Further analysis revealed that intranasal administration of rotenone also induced neurite degeneration of dopaminergic neurons in the substantia nigra. Our findings suggest that olfactory transport of environmental toxins induces neurodegeneration, and that olfactory dysfunction may be induced as an earliest symptom caused by inhaled neurotoxins.

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Other

  • 日本味と匂学会誌 （17巻2号2010年）

    2010.8

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Academic Activities

  • 日本味と匂学会・評議員

    2019.4

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