{"title":"Synaptic sabotage: How Tau and α-Synuclein undermine synaptic health.","authors":"Valerie Uytterhoeven, Patrik Verstreken, Eliana Nachman","doi":"10.1083/jcb.202409104","DOIUrl":"https://doi.org/10.1083/jcb.202409104","url":null,"abstract":"<p><p>Synaptic dysfunction is one of the earliest cellular defects observed in Alzheimer's disease (AD) and Parkinson's disease (PD), occurring before widespread protein aggregation, neuronal loss, and cognitive decline. While the field has focused on the aggregation of Tau and α-Synuclein (α-Syn), emerging evidence suggests that these proteins may drive presynaptic pathology even before their aggregation. Therefore, understanding the mechanisms by which Tau and α-Syn affect presynaptic terminals offers an opportunity for developing innovative therapeutics aimed at preserving synapses and potentially halting neurodegeneration. This review focuses on the molecular defects that converge on presynaptic dysfunction caused by Tau and α-Syn. Both proteins have physiological roles in synapses. However, during disease, they acquire abnormal functions due to aberrant interactions and mislocalization. We provide an overview of current research on different essential presynaptic pathways influenced by Tau and α-Syn. Finally, we highlight promising therapeutic targets aimed at maintaining synaptic function in both tauopathies and synucleinopathies.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 2","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882093","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}
{"title":"Structural response of microtubule and actin cytoskeletons to direct intracellular load.","authors":"Ryota Orii, Hirokazu Tanimoto","doi":"10.1083/jcb.202403136","DOIUrl":"10.1083/jcb.202403136","url":null,"abstract":"<p><p>Microtubule and actin are the two major cytoskeletal polymers that form organized functional structures in the interior of eukaryotic cells. Although the structural mechanics of the cytoskeleton has been extensively studied by direct manipulations in in vitro reconstitution systems, such unambiguous characterizations inside the living cell are sparse. Here, we report a comprehensive analysis of how the microtubule and actin cytoskeletons structurally respond to direct intracellular load. Ferrofluid-based intracellular magnetic tweezers reveal rheological properties of the microtubule complex primarily determined by filamentous actin. The strain fields of the microtubule complex and actin meshwork follow the same scaling, suggesting that the two cytoskeletal systems behave as an integrated elastic body. The structural responses of single microtubules to contact and remote forces further evidence that the individual microtubules are enclosed by the elastic medium of actin. These results, directly characterizing the microtubule and actin cytoskeletons as an interacting continuum throughout the cytoplasm, serve as a cornerstone for the physical understanding of intracellular organization.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 2","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11572716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638716","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}
Dahyana Arias Escayola, Chuyue Zhang, Emily Nischwitz, Leonard Schärfen, Kerstin Dörner, Korinna Straube, Ulrike Kutay, Falk Butter, Karla M Neugebauer
{"title":"Identification of coilin interactors reveals coordinated control of Cajal body number and structure.","authors":"Dahyana Arias Escayola, Chuyue Zhang, Emily Nischwitz, Leonard Schärfen, Kerstin Dörner, Korinna Straube, Ulrike Kutay, Falk Butter, Karla M Neugebauer","doi":"10.1083/jcb.202305081","DOIUrl":"10.1083/jcb.202305081","url":null,"abstract":"<p><p>The cell nucleus contains distinct biomolecular condensates that form at specific genetic loci, organize chromosomes in 3D space, and regulate RNA processing. Among these, Cajal bodies (CBs) require key \"scaffolding\" proteins for their assembly, which is not fully understood. Here, we employ proximity biotinylation, mass spectrometry, and functional screening to comprehensively identify and test the functions of CB components. We document 144 protein interactors of coilin, of which 70 were newly detected, and establish 25 players needed for CB assembly and/or maintenance. Surprisingly, the depletion of nine coilin interactors-mostly constituents of the 60S ribosome (RPLs)-increased CB number and caused subdomains defined by coilin and the survival motor neuron protein (SMN) to merge. These phenotypes were traceable to altered nuclear levels of dimethylarginine. Our data implicate RPL24 and other players in the regulation of CBs by modulating posttranslational modifications. Moreover, the prevalence of transcription factors among the identified components highlights roles for gene activity in CB assembly and nuclear positioning.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 2","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739767","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}
Kuan-Chung Su, Elena Radul, Nolan K Maier, Mary-Jane Tsang, Claire Goul, Brittania Moodie, Océane Marescal, Heather R Keys, Iain M Cheeseman
{"title":"Functional genetics reveals modulators of antimicrotubule drug sensitivity.","authors":"Kuan-Chung Su, Elena Radul, Nolan K Maier, Mary-Jane Tsang, Claire Goul, Brittania Moodie, Océane Marescal, Heather R Keys, Iain M Cheeseman","doi":"10.1083/jcb.202403065","DOIUrl":"10.1083/jcb.202403065","url":null,"abstract":"<p><p>Microtubules play essential roles in diverse cellular processes and are important pharmacological targets for treating human disease. Here, we sought to identify cellular factors that modulate the sensitivity of cells to antimicrotubule drugs. We conducted a genome-wide CRISPR/Cas9-based functional genetics screen in human cells treated with the microtubule-destabilizing drug nocodazole or the microtubule-stabilizing drug paclitaxel. We further conducted a focused secondary screen to test drug sensitivity for ∼1,400 gene targets across two distinct human cell lines and to additionally test sensitivity to the KIF11 inhibitor, STLC. These screens defined gene targets whose loss enhances or suppresses sensitivity to antimicrotubule drugs. In addition to gene targets whose loss sensitized cells to multiple compounds, we observed cases of differential sensitivity to specific compounds and differing requirements between cell lines. Our downstream molecular analysis further revealed additional roles for established microtubule-associated proteins and identified new players in microtubule function.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 2","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11590752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681868","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}
Florent Arbogast, Raquel Sal-Carro, Wacym Boufenghour, Quentin Frenger, Delphine Bouis, Louise Filippi De La Palavesa, Jean-Daniel Fauny, Olivier Griso, Hélène Puccio, Rebecca Fima, Thierry Huby, Emmanuel L Gautier, Anne Molitor, Raphaël Carapito, Seiamak Bahram, Nikolaus Romani, Björn E Clausen, Benjamin Voisin, Christopher G Mueller, Frédéric Gros, Vincent Flacher
{"title":"Epidermal maintenance of Langerhans cells relies on autophagy-regulated lipid metabolism.","authors":"Florent Arbogast, Raquel Sal-Carro, Wacym Boufenghour, Quentin Frenger, Delphine Bouis, Louise Filippi De La Palavesa, Jean-Daniel Fauny, Olivier Griso, Hélène Puccio, Rebecca Fima, Thierry Huby, Emmanuel L Gautier, Anne Molitor, Raphaël Carapito, Seiamak Bahram, Nikolaus Romani, Björn E Clausen, Benjamin Voisin, Christopher G Mueller, Frédéric Gros, Vincent Flacher","doi":"10.1083/jcb.202403178","DOIUrl":"10.1083/jcb.202403178","url":null,"abstract":"<p><p>Macroautophagy (often-named autophagy), a catabolic process involving autophagy-related (Atg) genes, prevents the accumulation of harmful cytoplasmic components and mobilizes energy reserves in long-lived and self-renewing cells. Autophagy deficiency affects antigen presentation in conventional dendritic cells (DCs) without impacting their survival. However, previous studies did not address epidermal Langerhans cells (LCs). Here, we demonstrate that deletion of either Atg5 or Atg7 in LCs leads to their gradual depletion. ATG5-deficient LCs showed metabolic dysregulation and accumulated neutral lipids. Despite increased mitochondrial respiratory capacity, they were unable to process lipids, eventually leading them to ferroptosis. Finally, metabolically impaired LCs upregulated proinflammatory transcripts and showed decreased expression of neuronal interaction receptors. Altogether, autophagy represents a critical regulator of lipid storage and metabolism in LCs, allowing their maintenance in the epidermis.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 2","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621231","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}
Christopher G Sorensen Turpin, Dillon Sloan, Marian LaForest, Lindsey Klebanow, Diana Mitchell, Aaron F Severson, Joshua N Bembenek
{"title":"Securin regulates the spatiotemporal dynamics of separase.","authors":"Christopher G Sorensen Turpin, Dillon Sloan, Marian LaForest, Lindsey Klebanow, Diana Mitchell, Aaron F Severson, Joshua N Bembenek","doi":"10.1083/jcb.202312099","DOIUrl":"10.1083/jcb.202312099","url":null,"abstract":"<p><p>Separase regulates multiple aspects of the metaphase-to-anaphase transition. Separase cleaves cohesin to allow chromosome segregation and localizes to vesicles to promote exocytosis. The anaphase-promoting complex/cyclosome (APC/C) activates separase by ubiquitinating its inhibitory chaperone, securin, triggering its degradation. How this pathway controls the exocytic function of separase is unknown. During meiosis I, securin is degraded over several minutes, while separase rapidly relocalizes from kinetochore structures at the spindle and cortex to sites of action on chromosomes and vesicles at anaphase onset. The loss of cohesin coincides with the relocalization of separase to the chromosome midbivalent at anaphase onset. APC/C depletion prevents separase relocalization, while securin depletion causes precocious separase relocalization. Expression of non-degradable securin inhibits chromosome segregation, exocytosis, and separase localization to vesicles but not to the anaphase spindle. We conclude that APC/C-mediated securin degradation controls separase localization. This spatiotemporal regulation will impact the effective local concentration of separase for more precise targeting of substrates in anaphase.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 2","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648289","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}
Eduardo Gameiro, Karla A Juárez-Núñez, Jia Jun Fung, Susmitha Shankar, Brian Luke, Anton Khmelinskii
{"title":"Genome-wide conditional degron libraries for functional genomics.","authors":"Eduardo Gameiro, Karla A Juárez-Núñez, Jia Jun Fung, Susmitha Shankar, Brian Luke, Anton Khmelinskii","doi":"10.1083/jcb.202409007","DOIUrl":"https://doi.org/10.1083/jcb.202409007","url":null,"abstract":"<p><p>Functional genomics with libraries of knockout alleles is limited to non-essential genes and convoluted by the potential accumulation of suppressor mutations in knockout backgrounds, which can lead to erroneous functional annotations. To address these limitations, we constructed genome-wide libraries of conditional alleles based on the auxin-inducible degron (AID) system for inducible degradation of AID-tagged proteins in the budding yeast Saccharomyces cerevisiae. First, we determined that N-terminal tagging is at least twice as likely to inadvertently impair protein function across the proteome. We thus constructed two libraries with over 5,600 essential and non-essential proteins fused at the C-terminus with an AID tag and an optional fluorescent protein. Approximately 90% of AID-tagged proteins were degraded in the presence of the auxin analog 5-Ph-IAA, with initial protein abundance and tag accessibility as limiting factors. Genome-wide screens for DNA damage response factors revealed a role for the glucose signaling factor GSF2 in resistance to hydroxyurea, highlighting how the AID libraries extend the yeast genetics toolbox.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 2","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846663","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}
Henrique Alves Domingos, Mattie Green, Vasileios R Ouzounidis, Cameron Finlayson, Bram Prevo, Dhanya K Cheerambathur
{"title":"The kinetochore protein KNL-1 regulates the actin cytoskeleton to control dendrite branching.","authors":"Henrique Alves Domingos, Mattie Green, Vasileios R Ouzounidis, Cameron Finlayson, Bram Prevo, Dhanya K Cheerambathur","doi":"10.1083/jcb.202311147","DOIUrl":"10.1083/jcb.202311147","url":null,"abstract":"<p><p>The function of the nervous system is intimately tied to its complex and highly interconnected architecture. Precise control of dendritic branching in individual neurons is central to building the complex structure of the nervous system. Here, we show that the kinetochore protein KNL-1 and its associated KMN (Knl1/Mis12/Ndc80 complex) network partners, typically known for their role in chromosome-microtubule coupling during mitosis, control dendrite branching in the Caenorhabditis elegans mechanosensory PVD neuron. KNL-1 restrains excess dendritic branching and promotes contact-dependent repulsion events, ensuring robust sensory behavior and preventing premature neurodegeneration. Unexpectedly, KNL-1 loss resulted in significant alterations of the actin cytoskeleton alongside changes in microtubule dynamics within dendrites. We show that KNL-1 modulates F-actin dynamics to generate proper dendrite architecture and that its N-terminus can initiate F-actin assembly. These findings reveal that the postmitotic neuronal KMN network acts to shape the developing nervous system by regulating the actin cytoskeleton and provide new insight into the mechanisms controlling dendrite architecture.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 2","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769302","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}
Alexander R Leydon, Benjamin Downing, Janet Solano Sanchez, Raphael Loll-Krippleber, Nathan M Belliveau, Ricard A Rodriguez-Mias, Andrew J Bauer, Isabella J Watson, Lena Bae, Judit Villén, Grant W Brown, Jennifer L Nemhauser
{"title":"A function of TPL/TBL1-type corepressors is to nucleate the assembly of the preinitiation complex.","authors":"Alexander R Leydon, Benjamin Downing, Janet Solano Sanchez, Raphael Loll-Krippleber, Nathan M Belliveau, Ricard A Rodriguez-Mias, Andrew J Bauer, Isabella J Watson, Lena Bae, Judit Villén, Grant W Brown, Jennifer L Nemhauser","doi":"10.1083/jcb.202404103","DOIUrl":"10.1083/jcb.202404103","url":null,"abstract":"<p><p>The plant corepressor TPL is recruited to diverse chromatin contexts, yet its mechanism of repression remains unclear. Previously, we leveraged the fact that TPL retains its function in a synthetic transcriptional circuit in the yeast model Saccharomyces cerevisiae to localize repressive function to two distinct domains. Here, we employed two unbiased whole-genome approaches to map the physical and genetic interactions of TPL at a repressed locus. We identified SPT4, SPT5, and SPT6 as necessary for repression with SPT4 acting as a bridge connecting TPL to SPT5 and SPT6. We discovered the association of multiple additional constituents of the transcriptional preinitiation complex at TPL-repressed promoters, specifically those involved early in transcription initiation. These findings were validated in yeast and plants, including a novel method to analyze the conditional loss of function of essential genes in plants. Our findings support a model where TPL nucleates preassembly of the transcription activation machinery to facilitate the rapid onset of transcription once repression is relieved.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 2","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11627113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142800933","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}
Roshan X Norman, Yu-Chia Chen, Emma E Recchia, Jonathan Loi, Quincy Rosemarie, Sydney L Lesko, Smit Patel, Nathan Sherer, Motoki Takaku, Mark E Burkard, Aussie Suzuki
{"title":"One step 4× and 12× 3D-ExM enables robust super-resolution microscopy of nanoscale cellular structures.","authors":"Roshan X Norman, Yu-Chia Chen, Emma E Recchia, Jonathan Loi, Quincy Rosemarie, Sydney L Lesko, Smit Patel, Nathan Sherer, Motoki Takaku, Mark E Burkard, Aussie Suzuki","doi":"10.1083/jcb.202407116","DOIUrl":"10.1083/jcb.202407116","url":null,"abstract":"<p><p>Super-resolution microscopy has become an indispensable tool across diverse research fields, offering unprecedented insights into biological architectures with nanometer scale resolution. Compared with traditional nanometer-scale imaging methods such as electron microscopy, super-resolution microscopy offers several advantages, including the simultaneous labeling of multiple target biomolecules with high specificity and simpler sample preparation, making it accessible to most researchers. In this study, we introduce two optimized methods of super-resolution imaging: 4-fold and 12-fold 3D-isotropic and preserved Expansion Microscopy (4× and 12× 3D-ExM). 3D-ExM is a straightforward expansion microscopy technique featuring a single-step process, providing robust and reproducible 3D isotropic expansion for both 2D and 3D cell culture models. With standard confocal microscopy, 12× 3D-ExM achieves a lateral resolution of <30 nm, enabling the visualization of nanoscale structures, including chromosomes, kinetochores, nuclear pore complexes, and Epstein-Barr virus particles. These results demonstrate that 3D-ExM provides cost-effective and user-friendly super-resolution microscopy, making it highly suitable for a wide range of cell biology research, including studies on cellular and chromatin architectures.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"224 2","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769247","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}