IF 64.5 1区生物学

Cell Pub Date : 2024-10-18 DOI: 10.1016/j.cell.2024.09.037

Kazuya Matsuo, Sefan Asamitsu, Kohei Maeda, Hiroyoshi Suzuki, Kosuke Kawakubo, Ginji Komiya, Kenta Kudo, Yusuke Sakai, Karin Hori, Susumu Ikenoshita, Shingo Usuki, Shiori Funahashi, Hideki Oizumi, Atsushi Takeda, Yasushi Kawata, Tomohiro Mizobata, Norifumi Shioda, Yasushi Yabuki

{"title":"RNA G-quadruplexes form scaffolds that promote neuropathological α-synuclein aggregation","authors":"Kazuya Matsuo, Sefan Asamitsu, Kohei Maeda, Hiroyoshi Suzuki, Kosuke Kawakubo, Ginji Komiya, Kenta Kudo, Yusuke Sakai, Karin Hori, Susumu Ikenoshita, Shingo Usuki, Shiori Funahashi, Hideki Oizumi, Atsushi Takeda, Yasushi Kawata, Tomohiro Mizobata, Norifumi Shioda, Yasushi Yabuki","doi":"10.1016/j.cell.2024.09.037","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.037","url":null,"abstract":"Synucleinopathies, including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, are triggered by α-synuclein aggregation, triggering progressive neurodegeneration. However, the intracellular α-synuclein aggregation mechanism remains unclear. Herein, we demonstrate that RNA G-quadruplex assembly forms scaffolds for α-synuclein aggregation, contributing to neurodegeneration. Purified α-synuclein binds RNA G-quadruplexes directly through the N terminus. RNA G-quadruplexes undergo Ca2+-induced phase separation and assembly, accelerating α-synuclein sol-gel phase transition. In α-synuclein preformed fibril-treated neurons, RNA G-quadruplex assembly comprising synaptic mRNAs co-aggregates with α-synuclein upon excess cytoplasmic Ca2+ influx, eliciting synaptic dysfunction. Forced RNA G-quadruplex assembly using an optogenetic approach evokes α-synuclein aggregation, causing neuronal dysfunction and neurodegeneration. The administration of 5-aminolevulinic acid, a protoporphyrin IX prodrug, prevents RNA G-quadruplex phase separation, thereby attenuating α-synuclein aggregation, neurodegeneration, and progressive motor deficits in α-synuclein preformed fibril-injected synucleinopathic mice. Therefore, Ca2+ influx-induced RNA G-quadruplex assembly accelerates α-synuclein phase transition and aggregation, potentially contributing to synucleinopathies.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"64 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Light-induced targeting enables proteomics on endogenous condensates 光诱导靶向技术实现了对内源性凝聚物的蛋白质组学研究

IF 64.5 1区生物学

Cell Pub Date : 2024-10-18 DOI: 10.1016/j.cell.2024.09.040

Choongman Lee, Andrea Quintana, Ida Suppanz, Alejandro Gomez-Auli, Gerhard Mittler, Ibrahim I. Cissé

引用次数: 0

From periphery to center stage: 50 years of advancements in innate immunity 从外围到中心舞台：先天性免疫 50 年的发展历程

IF 64.5 1区生物学

Cell Pub Date : 2024-10-18 DOI: 10.1016/j.cell.2024.10.013

Susan Carpenter, Luke A.J. O’Neill

引用次数: 0

PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes PLD3 和 PLD4 合成 S,S-BMP，这是一种能在溶酶体中实现脂质降解的关键磷脂

IF 64.5 1区生物学

Cell Pub Date : 2024-10-17 DOI: 10.1016/j.cell.2024.09.036

Shubham Singh, Ulrich E. Dransfeld, Yohannes A. Ambaw, Joshua Lopez-Scarim, Robert V. Farese, Tobias C. Walther

{"title":"PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes","authors":"Shubham Singh, Ulrich E. Dransfeld, Yohannes A. Ambaw, Joshua Lopez-Scarim, Robert V. Farese, Tobias C. Walther","doi":"10.1016/j.cell.2024.09.036","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.036","url":null,"abstract":"Bis(monoacylglycero)phosphate (BMP) is an abundant lysosomal phospholipid required for degradation of lipids, particularly gangliosides. Alterations in BMP levels are associated with neurodegenerative diseases. Unlike typical glycerophospholipids, lysosomal BMP has two chiral glycerol carbons in the S (rather than the R) stereo-conformation, protecting it from lysosomal degradation. How this unusual and yet crucial S,S-stereochemistry is achieved is unknown. Here, we report that phospholipases D3 and D4 (PLD3 and PLD4) synthesize lysosomal S,S-BMP, with either enzyme catalyzing the critical glycerol stereo-inversion reaction in vitro. Deletion of PLD3 or PLD4 markedly reduced BMP levels in cells or in murine tissues where either enzyme is highly expressed (brain for PLD3; spleen for PLD4), leading to gangliosidosis and lysosomal abnormalities. PLD3 mutants associated with neurodegenerative diseases, including risk of Alzheimer’s disease, diminished PLD3 catalytic activity. We conclude that PLD3/4 enzymes synthesize lysosomal S,S-BMP, a crucial lipid for maintaining brain health.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"124 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Decoding the brain: From neural representations to mechanistic models 解码大脑：从神经表征到机理模型

IF 64.5 1区生物学

Cell Pub Date : 2024-10-17 DOI: 10.1016/j.cell.2024.08.051

Mackenzie Weygandt Mathis, Adriana Perez Rotondo, Edward F. Chang, Andreas S. Tolias, Alexander Mathis

引用次数: 0

Understanding the neural basis of natural intelligence 了解自然智能的神经基础

IF 64.5 1区生物学

Cell Pub Date : 2024-10-17 DOI: 10.1016/j.cell.2024.07.049

Angelo Forli, Michael M. Yartsev

引用次数: 0

A line attractor encoding a persistent internal state requires neuropeptide signaling. 编码持久内部状态的线吸引子需要神经肽信号。

IF 45.5 1区生物学

Cell Pub Date : 2024-10-17 Epub Date: 2024-08-26 DOI: 10.1016/j.cell.2024.08.015

George Mountoufaris, Aditya Nair, Bin Yang, Dong-Wook Kim, Amit Vinograd, Samuel Kim, Scott W Linderman, David J Anderson

{"title":"A line attractor encoding a persistent internal state requires neuropeptide signaling.","authors":"George Mountoufaris, Aditya Nair, Bin Yang, Dong-Wook Kim, Amit Vinograd, Samuel Kim, Scott W Linderman, David J Anderson","doi":"10.1016/j.cell.2024.08.015","DOIUrl":"10.1016/j.cell.2024.08.015","url":null,"abstract":"Internal states drive survival behaviors, but their neural implementation is poorly understood. Recently, we identified a line attractor in the ventromedial hypothalamus (VMH) that represents a state of aggressiveness. Line attractors can be implemented by recurrent connectivity or neuromodulatory signaling, but evidence for the latter is scant. Here, we demonstrate that neuropeptidergic signaling is necessary for line attractor dynamics in this system by using cell-type-specific CRISPR-Cas9-based gene editing combined with single-cell calcium imaging. Co-disruption of receptors for oxytocin and vasopressin in adult VMH Esr1+ neurons that control aggression diminished attack, reduced persistent neural activity, and eliminated line attractor dynamics while only slightly reducing overall neural activity and sex- or behavior-specific tuning. These data identify a requisite role for neuropeptidergic signaling in implementing a behaviorally relevant line attractor in mammals. Our approach should facilitate mechanistic studies in neuroscience that bridge different levels of biological function and abstraction.","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"5998-6015.e18"},"PeriodicalIF":45.5,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11490375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A conserved fertilization complex bridges sperm and egg in vertebrates 脊椎动物中连接精子和卵子的保守受精复合体

IF 64.5 1区生物学

Cell Pub Date : 2024-10-17 DOI: 10.1016/j.cell.2024.09.035

Victoria E. Deneke, Andreas Blaha, Yonggang Lu, Johannes P. Suwita, Jonne M. Draper, Clara S. Phan, Karin Panser, Alexander Schleiffer, Laurine Jacob, Theresa Humer, Karel Stejskal, Gabriela Krssakova, Elisabeth Roitinger, Dominik Handler, Maki Kamoshita, Tyler D.R. Vance, Xinyin Wang, Joachim M. Surm, Yehu Moran, Jeffrey E. Lee, Andrea Pauli

{"title":"A conserved fertilization complex bridges sperm and egg in vertebrates","authors":"Victoria E. Deneke, Andreas Blaha, Yonggang Lu, Johannes P. Suwita, Jonne M. Draper, Clara S. Phan, Karin Panser, Alexander Schleiffer, Laurine Jacob, Theresa Humer, Karel Stejskal, Gabriela Krssakova, Elisabeth Roitinger, Dominik Handler, Maki Kamoshita, Tyler D.R. Vance, Xinyin Wang, Joachim M. Surm, Yehu Moran, Jeffrey E. Lee, Andrea Pauli","doi":"10.1016/j.cell.2024.09.035","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.035","url":null,"abstract":"Fertilization, the basis for sexual reproduction, culminates in the binding and fusion of sperm and egg. Although several proteins are known to be crucial for this process in vertebrates, the molecular mechanisms remain poorly understood. Using an AlphaFold-Multimer screen, we identified the protein Tmem81 as part of a conserved trimeric sperm complex with the essential fertilization factors Izumo1 and Spaca6. We demonstrate that Tmem81 is essential for male fertility in zebrafish and mice. In line with trimer formation, we show that Izumo1, Spaca6, and Tmem81 interact in zebrafish sperm and that the human orthologs interact in vitro. Notably, complex formation creates the binding site for the egg fertilization factor Bouncer in zebrafish. Together, our work presents a comprehensive model for fertilization across vertebrates, where a conserved sperm complex binds to divergent egg proteins—Bouncer in fish and JUNO in mammals—to mediate sperm-egg interaction.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"16 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In search of problems 寻找问题

IF 64.5 1区生物学

Cell Pub Date : 2024-10-17 DOI: 10.1016/j.cell.2024.09.017

Mu-ming Poo

引用次数: 0

The expanding world of neuroscience 不断扩大的神经科学世界

IF 64.5 1区生物学

Cell Pub Date : 2024-10-17 DOI: 10.1016/j.cell.2024.09.015

引用次数: 0

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