Updated on 2022/11/29

写真a

 
NITTA Yohei
 
Organization
Brain Research Institute Center for Bioresources Specially Appointed Assistant Professor
Title
Specially Appointed Assistant Professor
External link

Degree

  • 博士(理学) ( 2017.1   東京大学 )

Research Interests

  • drosophila

  • 神経変性

  • 脂質代謝

  • キノコ体

  • 神経発生

Research Areas

  • Life Science / Neuroscience-general

Research History (researchmap)

  • Niigata University   Brain Research Institute   Specially Appointed Assistant Professor

    2021.4

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  • Niigata University   Institute for Research Promotion Center for Transdisciplinary Research

    2018.4 - 2021.3

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  • Niigata University   Institute for Research Promotion Center for Transdisciplinary Research   Researcher

    2017.1 - 2018.3

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Research History

  • Niigata University   Center for Bioresources, Brain Research Institute   Specially Appointed Assistant Professor

    2021.4

 

Papers

  • Studies of neurodegenerative diseases using <i>Drosophila</i> and the development of novel approaches for their analysis Invited Reviewed

    Yohei Nitta, Atsushi Sugie

    Fly   16 ( 1 )   275 - 298   2022.12

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    Authorship:Lead author   Publishing type:Research paper (scientific journal)   Publisher:Informa UK Limited  

    DOI: 10.1080/19336934.2022.2087484

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  • A Quantitative Model of Sporadic Axonal Degeneration in the Drosophila Visual System. Reviewed International journal

    Mélisande Richard, Karolína Doubková, Yohei Nitta, Hiroki Kawai, Atsushi Sugie, Gaia Tavosanis

    The Journal of neuroscience : the official journal of the Society for Neuroscience   42 ( 24 )   4937 - 4952   2022.6

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

    In human neurodegenerative diseases, neurons undergo axonal degeneration months to years before they die. Here, we developed a system modeling early degenerative events in Drosophila adult photoreceptor cells. Thanks to the stereotypy of their axonal projections, this system delivers quantitative data on sporadic and progressive axonal degeneration of photoreceptor cells. Using this method, we show that exposure of adult female flies to a constant light stimulation for several days overcomes the intrinsic resilience of R7 photoreceptors and leads to progressive axonal degeneration. This was not associated with apoptosis. We furthermore provide evidence that loss of synaptic integrity between R7 and a postsynaptic partner preceded axonal degeneration, thus recapitulating features of human neurodegenerative diseases. Finally, our experiments uncovered a role of postsynaptic partners of R7 to initiate degeneration, suggesting that postsynaptic cells signal back to the photoreceptor to maintain axonal structure. This model can be used to dissect cellular and circuit mechanisms involved in the early events of axonal degeneration, allowing for a better understanding of how neurons cope with stress and lose their resilience capacities.SIGNIFICANCE STATEMENT Neurons can be active and functional for several years. In the course of aging and in disease conditions leading to neurodegeneration, subsets of neurons lose their resilience and start dying. What initiates this turning point at the cellular level is not clear. Here, we developed a model allowing to systematically describe this phase. The loss of synapses and axons represents an early and functionally relevant event toward degeneration. Using the ordered distribution of Drosophila photoreceptor axon terminals, we assembled a system to study sporadic initiation of axon loss and delineated a role for non-cell-autonomous activity regulation in the initiation of axon degeneration. This work will help shed light on key steps in the etiology of nonfamilial cases of neurodegenerative diseases.

    DOI: 10.1523/JNEUROSCI.2115-21.2022

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  • MeDUsA: A novel system for automated axon quantification to evaluate neuroaxonal degeneration

    Yohei Nitta, Hiroki Kawai, Jiro Osaka, Satoko Hakeda-Suzuki, Yoshitaka Nagai, Karolína Doubková, Takashi Suzuki, Gaia Tavosanis, Atsushi Sugie

    2021.10

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    Authorship:Lead author   Language:English   Publisher:Cold Spring Harbor Laboratory  

    Abstract

    Background

    Drosophila is an excellent model organism for studying human neurodegenerative diseases (NDs), and the rough eye phenotype (REP) assay is a convenient experimental system for analysing the toxicity of ectopically expressed human disease genes. However, the association between REP and axonal degeneration, an early sign of ND, remains unclear. To address this question, we developed a method to evaluate axonal degeneration by quantifying the number of retinal R7 axons in Drosophila; however, it requires expertise and is time-consuming. Therefore, there is a need for an easy-to-use software that can automatically quantify the axonal degeneration.

    Result

    We created MeDUsA (a ‘method for the quantification of degeneration using fly axons’), which is a standalone executable computer program based on Python that combines a pre-trained deep-learning masking tool with an axon terminal counting tool. This software automatically quantifies the number of axons from a confocal z-stack image series. Using this software, we have demonstrated for the first time directly that axons degenerate when the causative factors of NDs (αSyn, Tau, TDP-43, HTT) were expressed in the Drosophila eye. Furthermore, we compared axonal toxicity of the representative causative genes of NDs and their pathological alleles with REP and found no significant correlation between them.

    Conclusions

    MeDUsA rapidly and accurately quantifies axons in Drosophila eye. By simplifying and automating time-consuming manual efforts requiring significant expertise, it enables large-scale, complex research efforts on axonal degeneration, such as screening to identify genes or drugs that mediate axonal toxicity caused by ND disease proteins.

    DOI: 10.1101/2021.10.25.465674

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  • De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality. Reviewed International journal

    Masamune Sakamoto, Kazunori Sasaki, Atsushi Sugie, Yohei Nitta, Tetsuaki Kimura, Semra Gürsoy, Tayfun Cinleti, Mizue Iai, Toru Sengoku, Kazuhiro Ogata, Atsushi Suzuki, Nobuhiko Okamoto, Kazuhiro Iwama, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Atsushi Fujita, Kohei Hamanaka, Satoko Miyatake, Takeshi Mizuguchi, Masataka Taguri, Shuuichi Ito, Hidehisa Takahashi, Noriko Miyake, Naomichi Matsumoto

    Human molecular genetics   31 ( 1 )   69 - 81   2021.8

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    An optimal Golgi transport system is important for mammalian cells. The adenosine diphosphate (ADP) ribosylation factors (ARF) are key proteins for regulating cargo sorting at the Golgi network. In this family, ARF3 mainly works at the trans-Golgi network (TGN), and no ARF3-related phenotypes have yet been described in humans. We here report the clinical and genetic evaluations of two unrelated children with de novo pathogenic variants in the ARF3 gene: c.200A > T (p.Asp67Val) and c.296G > T (p.Arg99Leu). Although the affected individuals presented commonly with developmental delay, epilepsy, and brain abnormalities, there were differences in severity, clinical course, and brain lesions. In vitro subcellular localization assays revealed that the p.Arg99Leu mutant localized to Golgi apparatus, similar to the wild-type, whereas the p.Asp67Val mutant tended to show a disperse cytosolic pattern together with abnormally dispersed Golgi localization, similar to that observed in a known dominant negative variant (p.Thr31Asn). Pull-down assays revealed that the p.Asp67Val had a loss-of-function effect and the p.Arg99Leu variant had increased binding of the adaptor protein, Golgi-localized, γ-adaptin ear-containing, ARF-binding protein 1 (GGA1), supporting the gain of function. Furthermore, in vivo studies revealed that p.Asp67Val transfection led to lethality in flies. In contrast, flies expressing p.Arg99Leu had abnormal rough eye, as observed in the gain-of-function variant p.Gln71Leu. These data indicate that two ARF3 variants, the possibly loss-of-function p.Asp67Val and the gain-of-function p.Arg99Leu, both impair the Golgi transport system. Therefore, it may not be unreasonable that they showed different clinical features like diffuse brain atrophy (p.Asp67Val) and cerebellar hypoplasia (p.Arg99Leu).

    DOI: 10.1093/hmg/ddab224

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  • Glial insulin regulates cooperative or antagonistic Golden goal/Flamingo interactions during photoreceptor axon guidance Reviewed International journal

    Hiroki Takechi, Satoko Hakeda-Suzuki, Yohei Nitta, Yuichi Ishiwata, Riku Iwanaga, Makoto Sato, Atsushi Sugie, Takashi Suzuki

    eLife   10   2021.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:eLife Sciences Publications, Ltd  

    Transmembrane protein Golden goal (Gogo) interacts with atypical cadherin Flamingo to direct R8 photoreceptor axons in the <italic>Drosophila</italic> visual system. However, the precise mechanisms underlying Gogo regulation during columnar- and layer-specific R8 axon targeting are unknown. Our studies demonstrated that the insulin secreted from surface and cortex glia switches the phosphorylation status of Gogo, thereby regulating its two distinct functions. Non-phosphorylated Gogo mediates the initial recognition of the glial protrusion in the center of the medulla column, whereas phosphorylated Gogo suppresses radial filopodia extension by counteracting Flamingo to maintain a one axon to one column ratio. Later, Gogo expression ceases during the midpupal stage, thus allowing R8 filopodia to extend vertically into the M3 layer. These results demonstrate that the long- and short-range signaling between the glia and R8 axon growth cones regulates growth cone dynamics in a stepwise manner, and thus shape the entire organization of the visual system.

    DOI: 10.7554/elife.66718

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    Other Link: https://cdn.elifesciences.org/articles/66718/elife-66718-v1.xml

  • Degeneration of dopaminergic neurons and impaired intracellular trafficking in Atp13a2 deficient zebrafish Reviewed International journal

    Hiromi Nyuzuki, Shinji Ito, Keisuke Nagasaki, Yohei Nitta, Noriko Matsui, Akihiko Saitoh, Hideaki Matsui

    IBRO Reports   9   1 - 8   2020.6

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    ATP13A2 is the autosomal recessive causative gene for juvenile-onset Parkinson's disease (PARK9, Parkinson's disease 9), also known as Kufor-Rakeb syndrome. The disease is characterized by levodopa-responsive Parkinsonism, supranuclear gaze palsy, spasticity, and dementia. Previously, we have reported that Atp13a2 deficient medaka fish showed dopaminergic neurodegeneration and lysosomal dysfunction, indicating that lysosome-autophagy impairment might be one of the key pathogeneses of Parkinson's disease. Here, we established Atp13a2 deficient zebrafish using CRISPR/Cas9 gene editing. We found that the number of TH + neurons in the posterior tuberculum and the locus coeruleus significantly reduced (dopaminergic neurons, 64 % at 4 months and 37 % at 12 months, p < 0.001 and p < 0.05, respectively; norepinephrine neurons, 52 % at 4 months and 40 % at 12 months, p < 0.001 and p < 0.05, respectively) in Atp13a2 deficient zebrafish, proving the degeneration of dopaminergic neurons. In addition, we found the reduction (60 %, p < 0.05) of cathepsin D protein expression in Atp13a2 deficient zebrafish using immunoblot. Transmission electron microscopy analysis using middle diencephalon samples from Atp13a2 deficient zebrafish showed lysosome-like bodies with vesicle accumulation and fingerprint-like structures, suggesting lysosomal dysfunction. Furthermore, a significant reduction (p < 0.001) in protein expression annotated with vesicle fusion with Golgi apparatus in Atp13a2 deficient zebrafish by liquid-chromatography tandem mass spectrometry suggested intracellular trafficking impairment. Therefore, we concluded that Atp13a2 deficient zebrafish exhibited degeneration of dopaminergic neurons, lysosomal dysfunction and the possibility of intracellular trafficking impairment, which would be the key pathogenic mechanism underlying Parkinson's disease.

    DOI: 10.1016/j.ibror.2020.05.002

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  • Analysing the evolutional and functional differentiation of four types of Daphnia magna cryptochrome in Drosophila circadian clock. Reviewed International journal

    Yohei Nitta, Sayaka Matsui, Yukine Kato, Yosuke Kaga, Kenkichi Sugimoto, Atsushi Sugie

    Scientific reports   9 ( 1 )   8857 - 8857   2019.6

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    Cryptochrome (CRY) plays an important role in the input of circadian clocks in various species, but gene copies in each species are evolutionarily divergent. Type I CRYs function as a photoreceptor molecule in the central clock, whereas type II CRYs directly regulate the transcriptional activity of clock proteins. Functions of other types of animal CRYs in the molecular clock remain unknown. The water flea Daphnia magna contains four Cry genes. However, it is still difficult to analyse these four genes. In this study, we took advantage of powerful genetic resources available from Drosophila to investigate evolutionary and functional differentiation of CRY proteins between the two species. We report differences in subcellular localisation of each D. magna CRY protein when expressed in the Drosophila clock neuron. Circadian rhythm behavioural experiments revealed that D. magna CRYs are not functionally conserved in the Drosophila molecular clock. These findings provide a new perspective on the evolutionary conservation of CRY, as functions of the four D. magna CRY proteins have diverse subcellular localisation levels. Furthermore, molecular clocks of D. magna have been evolutionarily differentiated from those of Drosophila. This study highlights the extensive functional diversity existing among species in their complement of Cry genes.

    DOI: 10.1038/s41598-019-45410-w

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  • Identification of glaikit in a genome-wide expression profiling for axonal bifurcation of the mushroom body in Drosophila Reviewed

    Yohei Nitta, Atsushi Sugie

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   487 ( 4 )   898 - 902   2017.6

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Axonal branching is a fundamental requirement for sending electrical signals to multiple targets. However, despite the importance of axonal branching in neural development and function, the molecular mechanisms that control branch formation are poorly understood. Previous studies have hardly addressed the intracellular signaling cascade of axonal bifurcation characterized by growth cone splitting. Recently we reported that DISCO interacting protein 2 (DIP2) regulates bifurcation of mushroom body axons in Drosophila melanogaster. DIP2 mutant displays ectopic bifurcations in alpha/beta neurons. Taking advantage of this phenomenon, we tried to identify genes involved in branching formation by comparing the transcriptome of wild type with that of DIP2 RNAi flies. After the microarray analysis, Glaikit (Gkt), a member of the phospholipase D superfamily, was identified as a downstream target of DIP2 by RNAi against gkt and qRT-PCR experiment. Single cell MARCM analysis of gkt mutant phenocopied the ectopic axonal branches observed in DIP2 mutant. Furthermore, a genetic analysis between gkt and DIP2 revealed that gkt potentially acts in parallel with DIP2. In conclusion, we identified a novel gene underlying the axonal bifurcation process. (C) 2017 The Authors. Published by Elsevier Inc.

    DOI: 10.1016/j.bbrc.2017.04.150

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  • DISCO interacting protein 2 determines direction of axon projection under the regulation of c-Jun N-terminal kinase in the Drosophila mushroom body Reviewed

    Yohei Nitta, Atsushi Sugie

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   487 ( 1 )   116 - 121   2017.5

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Precisely controlled axon guidance for complex neuronal wiring is essential for appropriate neuronal function. c-Jun N-terminal kinase (INK) was found to play a role in axon guidance recently as well as in cell proliferation, protection and apoptosis. In spite of many genetic and molecular studies on these biological processes regulated by JNK, how JNK regulates axon guidance accurately has not been fully explained thus far. To address this question, we use the Drosophila mushroom body (MB) as a model since the alpha/beta axons project in two distinct directions. Here we show that DISCO interacting protein 2 (DIP2) is required for the accurate direction of axonal guidance. DIP2 expression is under the regulation of Basket (Bsk), the Drosophila homologue of JNK. We additionally found that the Bsk/DIP2 pathway is independent from the AP-I transcriptional factor complex pathway, which is directly activated by Bsk. In conclusion, our findings revealed DIP2 as a novel effector downstream of Bsk modulating the direction of axon projection. (C) 2017 The Authors. Published by Elsevier Inc.

    DOI: 10.1016/j.bbrc.2017.04.028

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  • DISCO Interacting Protein 2 regulates axonal bifurcation and guidance of Drosophila mushroom body neurons Reviewed

    Yohei Nitta, Daisuke Yamazaki, Atsushi Sugie, Makoto Hiroi, Tetsuya Tabata

    DEVELOPMENTAL BIOLOGY   421 ( 2 )   233 - 244   2017.1

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Axonal branching is one of the key processes within the enormous complexity of the nervous system to enable a single neuron to send information to multiple targets. However, the molecular mechanisms that control branch formation are poorly understood. In particular, previous studies have rarely addressed the mechanisms underlying axonal bifurcation, in which axons form new branches via splitting of the growth cone. We demonstrate that DISCO Interacting Protein 2 (DIP2) is required for precise axonal bifurcation in Drosophila mushroom body (MB) neurons by suppressing ectopic bifurcation and regulating the guidance of sister axons. We also found that DIP2 localize to the plasma membrane. Domain function analysis revealed that the AMP-synthetase domains of DIP2 are essential for its function, which may involve exerting a catalytic activity that modifies fatty acids. Genetic analysis and subsequent biochemical analysis suggested that DIP2 is involved in the fatty acid metabolization of acyl-CoA. Taken together, our results reveal a function of DIP2 in the developing nervous system and provide a potential functional relationship between fatty acid metabolism and axon morphogenesis.

    DOI: 10.1016/j.ydbio.2016.11.015

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  • The NAV2 homolog Sickie regulates F-actin-mediated axonal growth in Drosophila mushroom body neurons via the non-canonical Rac-Cofilin pathway (vol 141, pg 4716, 2015) Reviewed

    Takashi Abe, Daisuke Yamazaki, Satoshi Murakami, Makoto Hiroi, Yohei Nitta, Yuko Maeyama, Tetsuya Tabata

    DEVELOPMENT   142 ( 5 )   1021 - 1021   2015.3

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    Language:English   Publisher:COMPANY OF BIOLOGISTS LTD  

    DOI: 10.1242/dev.122713

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  • The Relationship between the Number of Students Enrolling in the Doctoral Program and Academic Research Achievements -Case Study of the Doctoral Program of the Graduate School of Science and Technology, Niigata University- Reviewed

    Yohei Nitta, Rie Funayama, Atsushi Sugie, Katsuyuki Hirai

    8   1 - 8   2021.3

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    Authorship:Lead author   Language:Japanese   Publishing type:Research paper (bulletin of university, research institution)  

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  • The NAV2 homolog Sickie regulates F-actin-mediated axonal growth in Drosophila mushroom body neurons via the non-canonical Rac-Cofilin pathway Reviewed

    Takashi Abe, Daisuke Yamazaki, Satoshi Murakami, Makoto Hiroi, Yohei Nitta, Yuko Maeyama, Tetsuya Tabata

    DEVELOPMENT   141 ( 24 )   4716 - 4728   2014.12

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    The Rac-Cofilin pathway is essential for cytoskeletal remodeling to control axonal development. Rac signals through the canonical Rac-Pak-LIMK pathway to suppress Cofilin-dependent axonal growth and through a Pak-independent non-canonical pathway to promote outgrowth. Whether this non-canonical pathway converges to promote Cofilin-dependent F-actin reorganization in axonal growth remains elusive. We demonstrate that Sickie, a homolog of the human microtubule-associated protein neuron navigator 2, cell-autonomously regulates axonal growth of Drosophila mushroom body (MB) neurons via the non-canonical pathway. Sickie was prominently expressed in the newborn F-actin-rich axons of MB neurons. A sickie mutant exhibited axonal growth defects, and its phenotypes were rescued by exogenous expression of Sickie. We observed phenotypic similarities and genetic interactions among sickie and Rac-Cofilin signaling components. Using the MARCM technique, distinct F-actin and phospho-Cofilin patterns were detected in developing axons mutant for sickie and Rac-Cofilin signaling regulators. The upregulation of Cofilin function alleviated the axonal defect of the sickie mutant. Epistasis analyses revealed that Sickie suppresses the LIMK overexpression phenotype and is required for Pak-independent Rac1 and Slingshot phosphatase to counteract LIMK. We propose that Sickie regulates F-actin-mediated axonal growth via the non-canonical Rac-Cofilin pathway in a Slingshot-dependent manner.

    DOI: 10.1242/dev.113308

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