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1دورية أكاديمية
المؤلفون: Yukio Imamura, Ayami Okuzumi, Saki Yoshinaga, Akiko Hiyama, Yoshiaki Furukawa, Tomohiro Miyasaka, Nobutaka Hattori, Nobuyuki Nukina
المصدر: Communications Biology, Vol 5, Iss 1, Pp 1-14 (2022)
مصطلحات موضوعية: Biology (General), QH301-705.5
الوصف: Quantum dot-labelling of preformed α-synuclein fibrils enables visualization of pharmacological effects on fibril seed spreading.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/2399-3642Test
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2دورية أكاديمية
المؤلفون: Hongsun Park, Tomoyuki Yamanaka, Yumiko Toyama, Atsushi Fujita, Hiroshi Doi, Takashi Nirasawa, Shigeo Murayama, Naomichi Matsumoto, Tomomi Shimogori, Masaya Ikegawa, Matti J. Haltia, Nobuyuki Nukina
المصدر: Acta Neuropathologica Communications, Vol 10, Iss 1, Pp 1-17 (2022)
مصطلحات موضوعية: NIID, Neuronal intranuclear inclusion, Hornerin, Amino acid analysis, Compositionally biased region, Low sequence complexity, Neurology. Diseases of the nervous system, RC346-429
الوصف: Abstract Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder, characterized by the presence of eosinophilic inclusions (NIIs) within nuclei of central and peripheral nervous system cells. This study aims to identify the components of NIIs, which have been difficult to analyze directly due to their insolubility. In order to establish a method to directly identify the components of NIIs, we first analyzed the huntingtin inclusion-rich fraction obtained from the brains of Huntington disease model mice. Although the sequence with expanded polyglutamine could not be identified by liquid-chromatography mass spectrometry, amino acid analysis revealed that glutamine of the huntingtin inclusion-rich fraction increased significantly. This is compatible with the calculated amino acid content of the transgene product. Therefore, we applied this method to analyze the NIIs of diseased human brains, which may have proteins with compositionally biased regions, and identified a serine-rich protein called hornerin. Since the analyzed NII-rich fraction was also serine-rich, we suggested hornerin as a major component of the NIIs. A specific distribution of hornerin in NIID was also investigated by Matrix-assisted laser desorption/ionization imaging mass spectrometry and immunofluorescence. Finally, we confirmed a variant of hornerin by whole-exome sequencing and DNA sequencing. This study suggests that hornerin may be related to the pathological process of this NIID, and the direct analysis of NIIs, especially by amino acid analysis using the NII-rich fractions, would contribute to a deeper understanding of the disease pathogenesis.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/2051-5960Test
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3دورية أكاديمية
المؤلفون: Hongsun Park, Tomoyuki Yamanaka, Nobuyuki Nukina
المصدر: Scientific Reports, Vol 12, Iss 1, Pp 1-13 (2022)
الوصف: Abstract Intrinsically disordered proteins (IDPs) have been in the spotlight for their unique properties, such as their lack of secondary structures and low sequence complexity. Alpha-synuclein and tau are representative disease-related IDPs with low complexity regions in their sequences, accumulating in the brains of patients with Parkinson disease and Alzheimer disease, respectively. Their heat resistance in particular was what attracted our attention. We assumed that there exist many other unidentified proteins that are resistant to heat-treatment, referred to as heat-stable proteins, which would also have low sequence complexity. In this study, we performed proteomic analysis of heat-stable proteins of mouse brains and found that proteins with compositionally biased regions are abundant in the heat-stable proteins. The proteins related to neurodegeneration are known to undergo different types of post-translational modifications (PTMs) such as phosphorylation and ubiquitination. We then investigated the heat-stability and aggregation properties of phosphorylated synuclein and tau with different phosphorylation sites. We suggest that PTMs can be important factors that determine the heat-stability and aggregation properties of a protein. IDPs identified in the heat-stable proteins of mouse brains would be candidates for the pathogenic proteins for neurodegeneration.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/2045-2322Test
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4دورية أكاديمية
المؤلفون: Tomoyuki Yamanaka, Haruko Miyazaki, Asako Tosaki, Sankar N. Maity, Tomomi Shimogori, Nobutaka Hattori, Nobuyuki Nukina
المصدر: Scientific Reports, Vol 10, Iss 1, Pp 1-14 (2020)
الوصف: Abstract A heterotrimeric transcription factor NF-Y is crucial for cell-cycle progression in various types of cells. In contrast, studies using NF-YA knockout mice have unveiled its essential role in endoplasmic reticulum (ER) homeostasis in neuronal cells. However, whether NF-Y modulates a different transcriptome to mediate distinct cellular functions remains obscure. Here, we knocked down NF-Y in two types of neuronal cells, neuro2a neuroblastoma cells and mouse brain striatal cells, and performed gene expression profiling. We found that down-regulated genes preferentially contained NF-Y-binding motifs in their proximal promoters, and notably enriched genes related to ER functions rather than those for cell cycle. This contrasts with the profiling data of HeLa and embryonic stem cells in which distinct down-regulation of cell cycle-related genes was observed. Clustering analysis further identified several functional clusters where populations of the down-regulated genes were highly distinct. Further analyses using chromatin immunoprecipitation and RNA-seq data revealed that the transcriptomic difference was not correlated with DNA binding of NF-Y but with splicing of NF-YA. These data suggest that neuronal cells have a different type of transcriptome in which ER-related genes are dominantly modulated by NF-Y, and imply that NF-YA splicing alteration could be involved in this cell type-specific gene modulation.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/2045-2322Test
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5دورية أكاديمية
المؤلفون: Motoaki Yanaizu, Chika Washizu, Nobuyuki Nukina, Jun-ichi Satoh, Yoshihiro Kino
المصدر: Scientific Reports, Vol 10, Iss 1, Pp 1-13 (2020)
الوصف: Abstract Genetic variations of TREM2 have been implicated as a risk factor of Alzheimer’s disease (AD). Recent studies suggest that the loss of TREM2 function compromises microglial responses to the accumulation of amyloid beta. Previously, we found that exon 3 of TREM2 is an alternative exon whose skipping leads to a reduction in full-length TREM2 protein by inducing nonsense-mediated mRNA decay. Here, we aimed to identify factors regulating TREM2 splicing. Using a panel of RNA-binding proteins, we found that exon 3 skipping of TREM2 was promoted by two paralogous proteins, CELF1 and CELF2, which were both linked previously with risk loci of AD. Although the overexpression of both CELF1 and CELF2 enhanced exon 3 skipping, only CELF2 reduced the expression of full-length TREM2 protein. Notably, the TREM2 ortholog in the green monkey, but not in the mouse, showed alternative splicing of exon 3 like human TREM2. Similarly, splicing regulation of exon 3 by CELF1/2 was found to be common to humans and monkeys. Using chimeric minigenes of human and mouse TREM2, we mapped a CELF-responsive sequence within intron 3 of human TREM2. Collectively, our results revealed a novel regulatory factor of TREM2 expression and highlighted a species-dependent difference of its regulation.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/2045-2322Test
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6دورية أكاديمية
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7دورية أكاديمية
المؤلفون: Nica Borgese, Francesca Navone, Nobuyuki Nukina, Tomoyuki Yamanaka
المصدر: Contact, Vol 4 (2021)
مصطلحات موضوعية: Biology (General), QH301-705.5, Biochemistry, QD415-436
الوصف: Nearly twenty years ago a mutation in the VAPB gene, resulting in a proline to serine substitution (p.P56S), was identified as the cause of a rare, slowly progressing, familial form of the motor neuron degenerative disease Amyotrophic Lateral Sclerosis (ALS). Since then, progress in unravelling the mechanistic basis of this mutation has proceeded in parallel with research on the VAP proteins and on their role in establishing membrane contact sites between the ER and other organelles. Analysis of the literature on cellular and animal models reviewed here supports the conclusion that P56S-VAPB, which is aggregation-prone, non-functional and unstable, is expressed at levels that are insufficient to support toxic gain-of-function or dominant negative effects within motor neurons. Instead, insufficient levels of the product of the single wild-type allele appear to be required for pathological effects, and may be the main driver of the disease. In light of the multiple interactions of the VAP proteins, we address the consequences of specific VAPB depletion and highlight various affected processes that could contribute to motor neuron degeneration. In the future, distinction of specific roles of each of the two VAP paralogues should help to further elucidate the basis of p.P56S familial ALS, as well as of other more common forms of the disease.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/2515-2564Test
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8دورية أكاديمية
المؤلفون: Ayami Okuzumi, Masaru Kurosawa, Taku Hatano, Masashi Takanashi, Shuuko Nojiri, Takeshi Fukuhara, Tomoyuki Yamanaka, Haruko Miyazaki, Saki Yoshinaga, Yoshiaki Furukawa, Tomomi Shimogori, Nobutaka Hattori, Nobuyuki Nukina
المصدر: Acta Neuropathologica Communications, Vol 6, Iss 1, Pp 1-15 (2018)
مصطلحات موضوعية: Rapid dissemination, A-syn, Propagation, Callosotomy, Neurology. Diseases of the nervous system, RC346-429
الوصف: Abstract Accumulating evidence suggests that the lesions of Parkinson’s disease (PD) expand due to transneuronal spreading of fibrils composed of misfolded alpha-synuclein (a-syn), over the course of 5–10 years. However, the precise mechanisms and the processes underlying the spread of these fibril seeds have not been clarified in vivo. Here, we investigated the speed of a-syn transmission, which has not been a focus of previous a-syn transmission experiments, and whether a-syn pathologies spread in a neural circuit–dependent manner in the mouse brain. We injected a-syn preformed fibrils (PFFs), which are seeds for the propagation of a-syn deposits, either before or after callosotomy, to disconnect bilateral hemispheric connections. In mice that underwent callosotomy before the injection, the propagation of a-syn pathology to the contralateral hemisphere was clearly reduced. In contrast, mice that underwent callosotomy 24 h after a-syn PFFs injection showed a-syn pathology similar to that seen in mice without callosotomy. These results suggest that a-syn seeds are rapidly disseminated through neuronal circuits immediately after seed injection, in a prion-like seeding experiment in vivo, although it is believed that clinical a-syn pathologies take years to spread throughout the brain. In addition, we found that botulinum toxin B blocked the transsynaptic transmission of a-syn seeds by specifically inactivating the synaptic vesicle fusion machinery. This study offers a novel concept regarding a-syn propagation, based on the Braak hypothesis, and also cautions that experimental transmission systems may be examining a unique type of transmission, which differs from the clinical disease state.
وصف الملف: electronic resource
العلاقة: http://link.springer.com/article/10.1186/s40478-018-0587-0Test; https://doaj.org/toc/2051-5960Test
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9دورية أكاديمية
المؤلفون: Gen Matsumoto, Tomonao Inobe, Takanori Amano, Kiyohito Murai, Nobuyuki Nukina, Nozomu Mori
المصدر: Scientific Reports, Vol 8, Iss 1, Pp 1-14 (2018)
الوصف: Abstract Accumulation of ubiquitinated protein aggregates is a common pathology associated with a number of neurodegenerative diseases and selective autophagy plays a critical role in their elimination. Although aging-related decreases in protein degradation properties may enhance protein aggregation, it remains unclear whether proteasome dysfunction is indispensable for ubiquitinated-protein aggregation in neurodegenerative diseases. Here, we show that N-oleoyl-dopamine and N-arachidonyl-dopamine, which are endogenous brain substances and belong to the N-acyldopamine (AcylDA) family, generate cellular inclusions through aggresome formation without proteasome inhibition. Although AcylDA itself does not inhibit proteasome activity in vitro, it activates the rearrangement of vimentin distribution to form a vimentin cage surrounding aggresomes and sequesters ubiquitinated proteins in aggresomes. The gene transcription of p62/SQSTM1 was significantly increased by AcylDAs, whereas the transcription of other ubiquitin-dependent autophagy receptors was unaffected. Genetic depletion of p62 resulted in the loss of ubiquitinated-protein sequestration in aggresomes, indicating that p62 is a critical component of aggresomes. Furthermore, AcylDAs accelerate the aggregation of mutant huntingtin exon 1 proteins. These results suggest that aggresome formation does not require proteasome dysfunction and AcylDA-induced aggresome formation may participate in forming cytoplasmic protein inclusions.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/2045-2322Test
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10دورية أكاديمية
المؤلفون: Fernande Freyermuth, Frédérique Rau, Yosuke Kokunai, Thomas Linke, Chantal Sellier, Masayuki Nakamori, Yoshihiro Kino, Ludovic Arandel, Arnaud Jollet, Christelle Thibault, Muriel Philipps, Serge Vicaire, Bernard Jost, Bjarne Udd, John W. Day, Denis Duboc, Karim Wahbi, Tsuyoshi Matsumura, Harutoshi Fujimura, Hideki Mochizuki, François Deryckere, Takashi Kimura, Nobuyuki Nukina, Shoichi Ishiura, Vincent Lacroix, Amandine Campan-Fournier, Vincent Navratil, Emilie Chautard, Didier Auboeuf, Minoru Horie, Keiji Imoto, Kuang-Yung Lee, Maurice S. Swanson, Adolfo Lopez de Munain, Shin Inada, Hideki Itoh, Kazuo Nakazawa, Takashi Ashihara, Eric Wang, Thomas Zimmer, Denis Furling, Masanori P. Takahashi, Nicolas Charlet-Berguerand
المصدر: Nature Communications, Vol 7, Iss 1, Pp 1-14 (2016)
مصطلحات موضوعية: Science
الوصف: Patients with myotonic dystrophy (MD) suffer from severe cardiac issues of unknown aetiology. Freyermuth et al. show that fatal changes in cardiac electrophysiological properties in humans and mice with MD may arise from misregulation of the alternative splicing of the cardiac Na+ channel SCN5Atranscript, resulting in expression of its fetal form.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/2041-1723Test
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