担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：eLife Sciences Publications, Ltd  

Autosomal dominant optic atrophy (DOA) is a progressive form of blindness caused by degeneration of retinal ganglion cells and their axons, mainly caused by mutations in the OPA1 mitochondrial dynamin like GTPase (OPA1) gene. OPA1 encodes a dynamin-like GTPase present in the mitochondrial inner membrane. When associated with OPA1 mutations, DOA can present not only ocular symptoms but also multi-organ symptoms (DOA plus). DOA plus often results from point mutations in the GTPase domain, which are assumed to have dominant-negative effects. However, the presence of mutations in the GTPase domain does not always result in DOA plus. Therefore, an experimental system to distinguish between DOA and DOA plus is needed. In this study, we found that loss-of-function mutations of the dOPA1 gene in Drosophila can imitate the pathology of optic nerve degeneration observed in DOA. We successfully rescued this degeneration by expressing the human OPA1 (hOPA1) gene, indicating that hOPA1 is functionally interchangeable with dOPA1 in the fly system. However, mutations previously identified did not ameliorate the dOPA1 deficiency phenotype. By expressing both WT and DOA plus mutant hOPA1 forms in the optic nerve of dOPA1 mutants, we observed that DOA plus mutations suppressed the rescue, facilitating the distinction between loss-of-function and dominant-negative mutations in hOPA1. This fly model aids in distinguishing DOA from DOA plus and guides initial hOPA1 mutation treatment strategies.

DOI： 10.7554/elife.87880.3

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その他リンク： https://cdn.elifesciences.org/articles/87880/elife-87880-v1.xml

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

<jats:title>SUMMARY</jats:title><jats:p>Neurons express many cell surface proteins as mutually binding “key-lock molecules” that can create synapses. However, the molecular mechanisms of how neurons make synapses only with preferred targets are not completely understood. Here we identified Side-IV and Beat-IIb, belonging to the<jats:italic>Drosophila</jats:italic>immunoglobulin superfamily, as a new key-lock combination capable of inducing synapse formation. Side-IV interaction with Beat-IIb transduces bifurcated signaling to Side-IV’s co-receptor, Kirre, and a synaptic scaffold protein, Dsyd-1. Localization and genetic interaction analyses revealed that Side-IV localizes subcellularly at synapse formations defined by Beat-IIa/b and anchors Dsyd-1. Our data demonstrate that a complex made up of Side-IV, Beat-IIb, Kirre, and Dsyd-1 not only narrows neuronal binding specificity but also recruits synapse formation factors Kirre and Dsyd-1 to restrict synapse formation loci and inhibit miswiring. We propose a mechanism by which key-lock molecules set a hierarchy of preference among neuronal pairs in a complex circuit in vivo.</jats:p>

DOI： 10.1016/j.celrep.2024.113798

PubMed

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記述言語：日本語   出版者・発行元：(公財)金原一郎記念医学医療振興財団  

＜文献概要＞ホスファチジルイノシトール4,5-ビスリン酸[PI(4,5)P2]は生体膜を構成するリン脂質の一種であり,細胞膜に局在して多種多様な機能を発揮する。また,PI(4,5)P2は分解されて二次メッセンジャーとしても機能する。本稿では,PI(4,5)P2の機能を紹介し,その代謝がいかに調節されているか,そしてその調節異常が引き起こす神経変性の分子基盤を述べる。

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press ({OUP})  

<jats:title>Abstract</jats:title>
<jats:p>Drosophila is an excellent model organism for studying human neurodegenerative diseases (NDs). However, there is still almost no experimental system that could directly observe the degeneration of neurons and automatically quantify axonal degeneration. In this study, we created MeDUsA (a ‘method for the quantification of degeneration using fly axons’), 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 retinal R7 axons in Drosophila from a confocal z-stack image series. Using this software, we were able to directly demonstrate that axons were degenerated by the representative causative genes of NDs for the first time in Drosophila. The fly retinal axon is an excellent experimental system that is capable of mimicking the pathology of axonal degeneration in human NDs. MeDUsA rapidly and accurately quantifies axons in Drosophila photoreceptor neurons. It enables large-scale research into axonal degeneration, including screening to identify genes or drugs that mediate axonal toxicity caused by ND proteins and diagnose the pathological significance of novel variants of human genes in axons.</jats:p>

DOI： 10.1093/hmg/ddac307

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その他リンク： https://academic.oup.com/hmg/article-pdf/32/9/1524/50045443/ddac307.pdf

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Genetics Society of Japan  

Neural activity-dependent synaptic plasticity is an important physiological phenomenon underlying environmental adaptation, memory and learning. However, its molecular basis, especially in presynaptic neurons, is not well understood. Previous studies have shown that the number of presynaptic active zones in the Drosophila melanogaster photoreceptor R8 is reversibly changed in an activity-dependent manner. During reversible synaptic changes, both synaptic disassembly and assembly processes were observed. Although we have established a paradigm for screening molecules involved in synaptic stability and several genes have been identified, genes involved in stimulus-dependent synaptic assembly are still elusive. Therefore, the aim of this study was to identify genes regulating stimulus-dependent synaptic assembly in Drosophila using an automated synapse quantification system. To this end, we performed RNAi screening against 300 memory-defective, synapse-related or transmembrane molecules in photoreceptor R8 neurons. Candidate genes were narrowed down to 27 genes in the first screen using presynaptic protein aggregation as a sign of synaptic disassembly. In the second screen, we directly quantified the decreasing synapse number using a GFP-tagged presynaptic protein marker. We utilized custom-made image analysis software, which automatically locates synapses and counts their number along individual R8 axons, and identified cirl as a candidate gene responsible for synaptic assembly. Finally, we present a new model of stimulus-dependent synaptic assembly through the interaction of cirl and its possible ligand, ten-a. This study demonstrates the feasibility of using the automated synapse quantification system to explore activity-dependent synaptic plasticity in Drosophila R8 photoreceptors in order to identify molecules involved in stimulus-dependent synaptic assembly.

DOI： 10.1266/ggs.22-00114

PubMed

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開催年月日： 2024年9月

記述言語：英語   会議種別：口頭発表（一般）  

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開催年月日： 2024年7月

記述言語：英語   会議種別：口頭発表（一般）  

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開催年月日： 2024年2月 - 2024年3月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2024年2月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2022年11月 - 2022年12月

記述言語：英語   会議種別：ポスター発表  

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