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1,489 results on '"Hasegawa, Masato"'

357. Calcium dysregulation contributes to neurodegeneration in FTLD patient iPSC-derived neurons.

Author

90379652, 50578002, 90455246, 90303817, 70332327, Imamura, Keiko, Sahara, Naruhiko, Kanaan, Nicholas M., Tsukita, Kayoko, Kondo, Takayuki, Kutoku, Yumiko, Ohsawa, Yutaka, Sunada, Yoshihide, Kawakami, Koichi, Hotta, Akitsu, Yawata, Satoshi, Watanabe, Dai, Hasegawa, Masato, Trojanowski, John Q., Lee, Virginia M.-Y., Suhara, Tetsuya, Higuchi, Makoto, Inoue, Haruhisa, 90379652, 50578002, 90455246, 90303817, 70332327, Imamura, Keiko, Sahara, Naruhiko, Kanaan, Nicholas M., Tsukita, Kayoko, Kondo, Takayuki, Kutoku, Yumiko, Ohsawa, Yutaka, Sunada, Yoshihide, Kawakami, Koichi, Hotta, Akitsu, Yawata, Satoshi, Watanabe, Dai, Hasegawa, Masato, Trojanowski, John Q., Lee, Virginia M.-Y., Suhara, Tetsuya, Higuchi, Makoto, and Inoue, Haruhisa

Abstract

Mutations in the gene MAPT encoding tau, a microtubules-associated protein, cause a subtype of familial neurodegenerative disorder, known as frontotemporal lobar degeneration tauopathy (FTLD-Tau), which presents with dementia and is characterized by atrophy in the frontal and temporal lobes of the brain. Although induced pluripotent stem cell (iPSC) technology has facilitated the investigation of phenotypes of FTLD-Tau patient neuronal cells in vitro, it remains unclear how FTLD-Tau patient neurons degenerate. Here, we established neuronal models of FTLD-Tau by Neurogenin2-induced direct neuronal differentiation from FTLD-Tau patient iPSCs. We found that FTLD-Tau neurons, either with an intronic MAPT mutation or with an exonic mutation, developed accumulation and extracellular release of misfolded tau followed by neuronal death, which we confirmed by correction of the intronic mutation with CRISPR/Cas9. FTLD-Tau neurons showed dysregulation of the augmentation of Ca[2+] transients evoked by electrical stimulation. Chemogenetic or pharmacological control of neuronal activity-relevant Ca[2+] influx by the introduction of designer receptors exclusively activated by designer drugs (DREADDs) or by the treatment with glutamate receptor blockers attenuated misfolded tau accumulation and neuronal death. These data suggest that neuronal activity may regulate neurodegeneration in tauopathy. This FTLD-Tau model provides mechanistic insights into tauopathy pathogenesis and potential avenues for treatments.

Published
2016

358. Calcium dysregulation contributes to neurodegeneration in FTLD patient iPSC-derived neurons

Author

Imamura, Keiko, primary, Sahara, Naruhiko, additional, Kanaan, Nicholas M., additional, Tsukita, Kayoko, additional, Kondo, Takayuki, additional, Kutoku, Yumiko, additional, Ohsawa, Yutaka, additional, Sunada, Yoshihide, additional, Kawakami, Koichi, additional, Hotta, Akitsu, additional, Yawata, Satoshi, additional, Watanabe, Dai, additional, Hasegawa, Masato, additional, Trojanowski, John Q., additional, Lee, Virginia M.-Y., additional, Suhara, Tetsuya, additional, Higuchi, Makoto, additional, and Inoue, Haruhisa, additional

Published
2016
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360. Exposure to bacterial endotoxin generates a distinct strain of α-synuclein fibril

Author

Kim, Changyoun, primary, Lv, Guohua, additional, Lee, Jun Sung, additional, Jung, Byung Chul, additional, Masuda-Suzukake, Masami, additional, Hong, Chul-Suk, additional, Valera, Elvira, additional, Lee, He-Jin, additional, Paik, Seung R., additional, Hasegawa, Masato, additional, Masliah, Eliezer, additional, Eliezer, David, additional, and Lee, Seung-Jae, additional

Published
2016
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364. TDP-43 in the hypoglossal nucleus identifies amyotrophic lateral sclerosis in behavioral variant frontotemporal dementia

Author

Halliday, Glenda M., primary, Kiernan, Matthew C., additional, Kril, Jillian J., additional, Mito, Remika, additional, Masuda-Suzukake, Masami, additional, Hasegawa, Masato, additional, McCann, Heather, additional, Bartley, Lauren, additional, Dobson-Stone, Carol, additional, Kwok, John B.J., additional, Hornberger, Michael, additional, Hodges, John R., additional, and Tan, Rachel H., additional

Published
2016
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369. Chorea as a clinical feature of the basophilic inclusion body disease subtype of fused-in-sarcoma-associated frontotemporal lobar degeneration

Author

Kawakami, Ito, primary, Kobayashi, Zen, additional, Arai, Tetsuaki, additional, Yokota, Osamu, additional, Nonaka, Takashi, additional, Aoki, Naoya, additional, Niizato, Kazuhiro, additional, Oshima, Kenichi, additional, Higashi, Shinji, additional, Katsuse, Omi, additional, Hosokawa, Masato, additional, Hasegawa, Masato, additional, and Akiyama, Haruhiko, additional

Published
2016
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370. Interplay between TDP-43 and docosahexaenoic acid-related processes in amyotrophic lateral sclerosis

Author

Cacabelos, Daniel, primary, Ayala, Victòria, additional, Granado-Serrano, Ana Belén, additional, Jové, Mariona, additional, Torres, Pascual, additional, Boada, Jordi, additional, Cabré, Rosanna, additional, Ramírez-Núñez, Omar, additional, Gonzalo, Hugo, additional, Soler-Cantero, Aranzazu, additional, Serrano, José Carlos Enrique, additional, Bellmunt, Maria Josep, additional, Romero, María Paz, additional, Motilva, María José, additional, Nonaka, Takashi, additional, Hasegawa, Masato, additional, Ferrer, Isidre, additional, Pamplona, Reinald, additional, and Portero-Otín, Manuel, additional

Published
2016
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373. Pathological tau deposition in Motor Neurone Disease and frontotemporal lobar degeneration associated with TDP-43 proteinopathy

Author

Behrouzi, Roya, primary, Liu, Xiawei, additional, Wu, Dongyue, additional, Robinson, Andrew C., additional, Tanaguchi-Watanabe, Sayuri, additional, Rollinson, Sara, additional, Shi, Jing, additional, Tian, Jinzhou, additional, Hamdalla, Hisham H. M., additional, Ealing, John, additional, Richardson, Anna, additional, Jones, Matthew, additional, Pickering-Brown, Stuart, additional, Davidson, Yvonne S., additional, Strong, Michael J., additional, Hasegawa, Masato, additional, Snowden, Julie S., additional, and Mann, David M. A., additional

Published
2016
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376. Phosphorylation of TAR DNA-binding Protein of 43 kDa (TDP-43) by Truncated Casein Kinase 1δ Triggers Mislocalization and Accumulation of TDP-43

Author

Nonaka, Takashi, primary, Suzuki, Genjiro, additional, Tanaka, Yoshinori, additional, Kametani, Fuyuki, additional, Hirai, Shinobu, additional, Okado, Haruo, additional, Miyashita, Tomoyuki, additional, Saitoe, Minoru, additional, Akiyama, Haruhiko, additional, Masai, Hisao, additional, and Hasegawa, Masato, additional

Published
2016
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388. N -Methyl- D -Aspartate Receptor Link to the MAP Kinase Pathway in Cortical and Hippocampal Neurons and Microglia Is Dependent on Calcium Sensors and Is Blocked by α-Synuclein, Tau, and Phospho-Tau in Non-transgenic and Transgenic APPSw,Ind Mice

Author

Franco, Rafael, Aguinaga, David, Reyes, Irene, Canela, Enric I., Lillo, Jaume, Tarutani, Airi, Hasegawa, Masato, del Ser-Badia, Anna, del Rio, José A., Kreutz, Michael R., Saura, Carlos A., and Navarro, Gemma

Subjects
METHYL aspartate receptors, HIPPOCAMPUS physiology, SYNUCLEINS
Abstract

N -methyl-D-aspartate receptors (NMDARs) respond to glutamate to allow the influx of calcium ions and the signaling to the mitogen-activated protein kinase (MAPK) cascade. Both MAPK- and Ca2+-mediated events are important for both neurotransmission and neural cell function and fate. Using a heterologous expression system, we demonstrate that NMDAR may interact with the EF-hand calcium-binding proteins calmodulin, calneuron-1, and NCS1 but not with caldendrin. NMDARs were present in primary cultures of both neurons and microglia from cortex and hippocampus. Calmodulin in microglia, and calmodulin and NCS1 in neurons, are necessary for NMDA-induced MAP kinase pathway activation. Remarkably, signaling to the MAP kinase pathway was blunted in primary cultures of cortical and hippocampal neurons and microglia from wild-type animals by proteins involved in neurodegenerative diseases: α-synuclein, Tau, and p-Tau. A similar blockade by pathogenic proteins was found using samples from the APPSw,Ind transgenic Alzheimer’s disease model. Interestingly, a very marked increase in NMDAR–NCS1 complexes was identified in neurons and a marked increase of both NMDAR–NCS1 and NMDAR–CaM complexes was identified in microglia from the transgenic mice. The results show that α-synuclein, Tau, and p-Tau disrupt the signaling of NMDAR to the MAPK pathway and that calcium sensors are important for NMDAR function both in neurons and microglia. Finally, it should be noted that the expression of receptor–calcium sensor complexes, specially those involving NCS1, is altered in neural cells from APPSw,Ind mouse embryos/pups. [ABSTRACT FROM AUTHOR]

Published
2018
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389. Frontotemporal dementia with trans‐activation response DNA‐binding protein 43 presenting with catatonic syndrome.

Author

Watanabe, Ryohei, Kawakami, Ito, Onaya, Mitsumoto, Higashi, Shinji, Arai, Nobutaka, Akiyama, Haruhiko, Hasegawa, Masato, and Arai, Tetsuaki

Subjects
FRONTOTEMPORAL dementia, DNA-binding proteins, CATATONIA, CEREBRAL cortex, PSYCHIATRIC drugs
Abstract

Catatonia is a clinical syndrome characterized by symptoms such as immobility, mutism, stupor, stereotypy, echophenomena, catalepsy, automatic obedience, posturing, negativism, gegenhalten and ambitendency. This syndrome occurs mostly in mood disorder and schizophrenic patients, and is related to neuronal dysfunction involving the frontal lobe. Some cases of frontotemporal dementia (FTD) with catatonia have been reported, but these cases were not examined by autopsy. Here, we report on a FTD case which showed catatonia after the first episode of brief psychotic disorder. At the age of 58, the patient had a sudden onset of disorganized behavior and meaningless speech. Psychotropic drugs were effective for catatonic symptoms. However, after remission apathy, hyperorality, socially inappropriate behavior, hoarding, and an instinctive grasp reaction appeared and persisted. Brain MRI showed significant atrophy of the bilateral fronto‐temporal lobes. A neuropathological examination revealed extensive trans‐activation response DNA‐binding protein 43 (TDP‐43) positive neurocytoplasmic inclusions and dystrophic neurites in the brain, including the cerebral cortex, basal ganglia, and brainstem. Pathological diagnosis was frontotemporal lobar degeneration (FTLD) with TDP‐43 (FTLD‐TDP) type C, which was also confirmed by the band pattern of C‐terminal fragments of TDP‐43 on western blotting of sarkosyl‐insoluble fractions extracted from the frozen brain. Dysfunction of the thalamus, globus pallidus, supplementary motor area, amygdala and cingulate cortex have been said to be related to the catatonic syndrome. In this case, these areas were affected, showing abnormal TDP‐43‐positive structures. Further studies are expected to confirm further clinical ‐ pathological correlations to FTLD. [ABSTRACT FROM AUTHOR]

Published
2018
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390. Pathological and immunoblot analysis of phosphorylated TDP‐43 in sporadic amyotrophic lateral sclerosis with pallido‐nigro‐luysian degeneration.

Author

Uchino, Akiko, Ogino, Mieko, Takahashi‐Fujigasaki, Junko, Oonuma, Saori, Kanazawa, Naomi, Kajita, Sabine, Ichinoe, Masaaki, Hasegawa, Masato, Nishiyama, Kazutoshi, and Murayama, Shigeo

Subjects
AMYOTROPHIC lateral sclerosis, IMMUNOBLOTTING, DNA-binding proteins, PARKINSON'S disease diagnosis, SYNUCLEINS, PATIENTS
Abstract

Transactivation response DNA‐binding protein 43 kDa (TDP‐43) is a key protein of sporadic amyotrophic lateral sclerosis (ALS), and phosphorylated form of TDP‐43 (p‐TDP‐43) is a major pathological protein that accumulates in sporadic ALS. p‐TDP‐43 is found not only in primary motor neurons, but often propagates to non‐motor systems as well. However, pallido‐nigro‐luysian (PNL) degeneration (PNLD) is rarely associated with ALS. We describe here a 68‐year‐old ALS patient presenting severe PNLD. He had difficulty walking due to poor movement of his right leg, and was diagnosed as having Parkinson’s disease because of akinesia. About 2 years after onset, weakness of his left hand and leg led to a diagnosis of ALS. Tube feeding and non‐invasive positive‐pressure ventilation were initiated. He died of respiratory failure at the age of 71. There was no family history of either neurological disorders or dementia. Neuropathological examination revealed severe loss of neurons and gliosis in the PNL system in addition to the upper and lower motor neuron system. p‐TDP‐43 pathology was widespread in the PNL and motor neuron systems and also in the amygdala and hippocampus where no significant gliosis or neuronal loss was detected. Synuclein pathology was not observed in the investigated areas. Immunoblot analysis of p‐TDP‐43 C‐terminal fragments showed a type B band pattern consistent with sporadic ALS. This is the first case of ALS with PNLD, in which p‐TDP‐43 distribution was widespread in the hippocampal formation (Nishihira type 2 and Brettschneider stage 4), and the type B immunoblot pattern was confirmed. Our case indicated that the PNL system can be involved in the disease process in sporadic ALS cases, although rarely. We also reviewed previous autopsy cases of ALS with PNLD to clarify the clinicopathological features. [ABSTRACT FROM AUTHOR]

Published
2018
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391. Molecular mechanisms of the co‐deposition of multiple pathological proteins in neurodegenerative diseases.

Author

Nonaka, Takashi, Masuda‐Suzukake, Masami, and Hasegawa, Masato

Subjects
NEURODEGENERATION, TAU proteins, ALPHA-synuclein, NEUROLOGICAL disorders, DISEASE progression, DEGENERATION (Pathology)
Abstract

Intracellular inclusions composed of abnormal protein aggregates are one of the neuropathological features of neurodegenerative diseases, and the formation of intracellular aggregates is believed to be associated with neurodegeneration leading to the onset of these diseases. In typical or pure cases, characteristic pathologies with one particular protein, such as tau, alpha‐synuclein or trans‐activation response DNA protein 43 (TDP‐43), can be observed in brains of patients. On the other hand, multiple protein pathologies co‐exist in many cases, raising the possibility that they may influence each other reciprocally in the pathogenesis and progression of the diseases. However, the molecular mechanisms through which these proteins interact with each other and through which they are co‐deposited in brains of patients remain poorly understood. In this review, we focus on the mechanisms of deposition of multiple pathological proteins, such as tau, alpha‐synuclein and/or TDP‐43, and on co‐deposition models of these proteins in vitro and in vivo intended to recapitulate the multiple pathologies found in diseased brains. [ABSTRACT FROM AUTHOR]

Published
2018
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394. Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau

Author

Taniguchi-Watanabe, Sayuri, primary, Arai, Tetsuaki, additional, Kametani, Fuyuki, additional, Nonaka, Takashi, additional, Masuda-Suzukake, Masami, additional, Tarutani, Airi, additional, Murayama, Shigeo, additional, Saito, Yuko, additional, Arima, Kunimasa, additional, Yoshida, Mari, additional, Akiyama, Haruhiko, additional, Robinson, Andrew, additional, Mann, David M. A., additional, Iwatsubo, Takeshi, additional, and Hasegawa, Masato, additional

Published
2015
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400. Wild-Type Monomeric α:-Synuclein Can Impair Vesicle Endocytosis and Synaptic Fidelity via Tubulin Polymerization at the Calyx of Held.

Author

Kohgaku Eguchi, Zacharie Taoufiq, Thorn-Seshold, Oliver, Trauner, Dirk, Hasegawa, Masato, and Takahashi, Tomoyuki

Subjects
SYNUCLEINS, SYNAPTIC vesicles, ENDOCYTOSIS, POLYMERIZATION, TUBULINS, CALYX
Abstract

α-Synuclein is a presynaptic protein the function of which has yet to be identified, but its neuronal content increases in patients of synucleinopathies including Parkinson's disease. Chronic overexpression of α-synuclein reportedly expresses various phenotypes of synaptic dysfunction, but the primary target of its toxicity has not been determined. To investigate this, we acutely loaded human recombinant α-synuclein or its pathological mutants in their monomeric forms into the calyces of Held presynaptic terminals in slices from auditorily mature and immature rats of either sex. Membrane capacitance measurements revealed significant and specific inhibitory effects of WT monomeric α-synuclein on vesicle endocytosis throughout development. However, the α-synuclein A53T mutant affected vesicle endocytosis only at immature calyces, whereas the A30P mutant had no effect throughout. The endocytic impairment by WT α-synuclein was rescued by intraterminal coloading of the microtubule (MT) polymerization blocker nocodazole. Furthermore, it was reversibly rescued by presynaptically loaded photostatin-1, a photoswitcheable inhibitor of MT polymerization, in a light-wavelength-dependent manner. In contrast, endocytic inhibition by the A53T mutant at immature calyces was not rescued by nocodazole. Functionally, presynaptically loaded WT α-synuclein had no effect on basal synaptic transmission evoked at a low frequency, but significantly attenuated exocytosis and impaired the fidelity of neurotransmission during prolonged high-frequency stimulation. We conclude that monomeric WT α-synuclein primarily inhibits vesicle endocytosis via MT overassembly, thereby impairing high-frequency neurotransmission. [ABSTRACT FROM AUTHOR]

Published
2017
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