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https://read.qxmd.com/read/38447793/swedish-alzheimer-s-disease-variant-perturbs-activity-of-retrograde-molecular-motors-and-causes-widespread-derangement-of-axonal-transport-pathways
#1
JOURNAL ARTICLE
Monica Feole, Victorio M Pozo Devoto, Neda Dragišić, Cayetana Arnaiz, Julieta Bianchelli, Kateřina Texlová, Kristina Kovačovicova, Jan S Novotny, Daniel Havas, Tomas L Falzone, Gorazd B Stokin
Experimental studies in flies, mice, and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimer's disease (AD). The mechanisms underlying these impairments in axonal transport, however, remain poorly understood. Here we report that the Swedish familial AD mutation causes a standstill of the Amyloid Precursor Protein (APP) in the axons at the expense of its reduced anterograde transport. The standstill reflects the perturbed directionality of the axonal transport of APP, which spends significantly more time traveling in the retrograde direction...
March 4, 2024: Journal of Biological Chemistry
https://read.qxmd.com/read/38407313/dynein-and-dynactin-move-long-range-but-are-delivered-separately-to-the-axon-tip
#2
JOURNAL ARTICLE
Alexander D Fellows, Michaela Bruntraeger, Thomas Burgold, Andrew R Bassett, Andrew P Carter
Axonal transport is essential for neuronal survival. This is driven by microtubule motors including dynein, which transports cargo from the axon tip back to the cell body. This function requires its cofactor dynactin and regulators LIS1 and NDEL1. Due to difficulties imaging dynein at a single-molecule level, it is unclear how this motor and its regulators coordinate transport along the length of the axon. Here, we use a neuron-inducible human stem cell line (NGN2-OPTi-OX) to endogenously tag dynein components and visualize them at a near-single molecule regime...
May 6, 2024: Journal of Cell Biology
https://read.qxmd.com/read/38323995/rab32-family-proteins-regulate-autophagosomal-components-recycling
#3
JOURNAL ARTICLE
Zhe Wu, Huilin Que, Chuangpeng Li, Li Yan, Shixuan Wang, Yueguang Rong
In autophagy, autophagosomes deliver the lumenal contents to lysosomes for degradation via autophagosome-lysosome fusion. In contrast, autophagosome outer membrane components were recycled via autophagosomal components recycling (ACR), which is mediated by the recycler complex. The recycler complex, composed of SNX4, SNX5, and SNX17, cooperate with the dynein-dynactin complex to mediate ACR. However, how ACR is regulated remains unknown. Here, we found that Rab32 family proteins localize to autolysosomes and are required for ACR, rather than other autophagosomal or lysosomal Rab proteins...
March 4, 2024: Journal of Cell Biology
https://read.qxmd.com/read/38311779/dysregulation-of-stress-granule-dynamics-by-dctn1-deficiency-exacerbates-tdp-43-pathology-in-drosophila-models-of-als-ftd
#4
JOURNAL ARTICLE
Tetsuhiro Ueda, Toshihide Takeuchi, Nobuhiro Fujikake, Mari Suzuki, Eiko N Minakawa, Morio Ueyama, Yuzo Fujino, Nobuyuki Kimura, Seiichi Nagano, Akio Yokoseki, Osamu Onodera, Hideki Mochizuki, Toshiki Mizuno, Keiji Wada, Yoshitaka Nagai
The abnormal aggregation of TDP-43 into cytoplasmic inclusions in affected neurons is a major pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 is aberrantly accumulated in the neurons of most patients with sporadic ALS/FTD and other TDP-43 proteinopathies, how TDP-43 forms cytoplasmic aggregates remains unknown. In this study, we show that a deficiency in DCTN1, a subunit of the microtubule-associated motor protein complex dynactin, perturbs the dynamics of stress granules and drives the formation of TDP-43 cytoplasmic aggregation in cultured cells, leading to the exacerbation of TDP-43 pathology and neurodegeneration in vivo...
February 4, 2024: Acta Neuropathologica Communications
https://read.qxmd.com/read/38297086/tropomyosin-1-i-c-coordinates-kinesin-1-and-dynein-motors-during-oskar-mrna-transport
#5
JOURNAL ARTICLE
Simone Heber, Mark A McClintock, Bernd Simon, Eve Mehtab, Karine Lapouge, Janosch Hennig, Simon L Bullock, Anne Ephrussi
Dynein and kinesin motors mediate long-range intracellular transport, translocating towards microtubule minus and plus ends, respectively. Cargoes often undergo bidirectional transport by binding to both motors simultaneously. However, it is not known how motor activities are coordinated in such circumstances. In the Drosophila female germline, sequential activities of the dynein-dynactin-BicD-Egalitarian (DDBE) complex and of kinesin-1 deliver oskar messenger RNA from nurse cells to the oocyte, and within the oocyte to the posterior pole...
January 31, 2024: Nature Structural & Molecular Biology
https://read.qxmd.com/read/38267040/wild-type-dctn1-suppresses-the-aggregation-of-dctn1-mutants-associated-with-perry-disease
#6
JOURNAL ARTICLE
Yuto Fukui, Hisashi Shirakawa, Shuji Kaneko, Kazuki Nagayasu
Perry disease, a rare autosomal dominant neurodegenerative disorder, is characterized by parkinsonism, depression or apathy, unexpected weight loss, and central hypoventilation. Genetic analyses have revealed a strong association between point mutations in the dynactin I gene (DCTN1) coding p150glued and Perry disease. Although previous reports have suggested a critical role of p150glued aggregation in Perry disease pathology, whether and how p150glued mutations affect protein aggregation is not fully understood...
2024: Biological & Pharmaceutical Bulletin
https://read.qxmd.com/read/38264934/role-of-bicdr-in-bristle-shaft-construction-and-support-of-bicd-functions
#7
JOURNAL ARTICLE
Aleksandra Jejina, Yeniffer Ayala, Dirk Beuchle, Thomas Höhener, Ruth E Dörig, Paula Vazquez-Pianzola, Greco Hernández, Beat Suter
Cell polarization requires asymmetric localization of numerous mRNAs, proteins, and organelles. The movement of cargo towards the minus end of microtubules mostly depends on cytoplasmic dynein motors. In the dynein/dynactin/Bicaudal-D transport machinery, Bicaudal-D (BicD) links the cargo to the motor. Here we focus on the role of Drosophila BicD-related (BicDR) in the development of the long bristles. Together with BicD, it contributes to the organization and stability of the actin cytoskeleton in the not-yet chitinized bristle shaft...
January 24, 2024: Journal of Cell Science
https://read.qxmd.com/read/38240798/single-molecule-imaging-of-stochastic-interactions-that-drive-dynein-activation-and-cargo-movement-in-cells
#8
JOURNAL ARTICLE
Nireekshit Addanki Tirumala, Gregory Michael Ian Redpath, Sarah Viktoria Skerhut, Pritha Dolai, Natasha Kapoor-Kaushik, Nicholas Ariotti, K Vijay Kumar, Vaishnavi Ananthanarayanan
Cytoplasmic dynein 1 (dynein) is the primary minus end-directed motor protein in most eukaryotic cells. Dynein remains in an inactive conformation until the formation of a tripartite complex comprising dynein, its regulator dynactin, and a cargo adaptor. How this process of dynein activation occurs is unclear since it entails the formation of a three-protein complex inside the crowded environs of a cell. Here, we employed live-cell, single-molecule imaging to visualize and track fluorescently tagged dynein...
March 4, 2024: Journal of Cell Biology
https://read.qxmd.com/read/38117588/ninein-promotes-f-actin-cup-formation-and-inward-phagosome-movement-during-phagocytosis-in-macrophages
#9
JOURNAL ARTICLE
Safia Omer, Jiahao Li, Claire X Yang, Rene E Harrison
Phagocytosis by macrophages is a highly polarized process to destroy large target cells. Binding to particles induces extensive cortical actin-generated forces that drive the formation of elaborate pseudopods around the target particle. Post-internalization, the resultant phagosome is driven towards the cell interior on microtubules (MTs) by cytoplasmic dynein. However, it is unclear whether dynein and cargo-adaptors contribute to the earlier steps of particle internalization and phagosome formation. Here we reveal that ninein, a MT minus-end-associated protein that localizes to the centrosome, is also present at the phagocytic cup in macrophages...
December 20, 2023: Molecular Biology of the Cell
https://read.qxmd.com/read/38076961/human-dynein-dynactin-is-a-fast-processive-motor-in-living-cells
#10
Vikash Verma, Patricia Wadsworth, Thomas J Maresca
Minus-end directed transport along microtubules in eukaryotes is primarily mediated by cytoplasmic dynein and its cofactor dynactin. Significant advances have been made in recent years characterizing human dynein-dynactin structure and function using in vitro assays, however, there is limited knowledge about the motile properties and functional organization of dynein-dynactin in living human cells. Total internal reflection fluorescence microscopy (TIRFM) of CRISPR-engineered human cells is employed here to visualize fluorescently tagged dynein heavy chain (DHC) and p50 with high spatio-temporal resolution...
November 29, 2023: bioRxiv
https://read.qxmd.com/read/37991893/branched-microtubule-nucleation-and-dynein-transport-organize-rangtp-asters-in-xenopus-laevis-egg-extract
#11
JOURNAL ARTICLE
Jacopo Scrofani, Felix Ruhnow, Wei-Xiang Chew, Davide Normanno, Francois Nedelec, Thomas Surrey, Isabelle Vernos
Chromosome segregation relies on the correct assembly of a bipolar spindle. Spindle pole self-organization requires dynein-dependent microtubule transport along other microtubules. However, during M-phase RanGTP triggers microtubule nucleation and branching generating polarized arrays with non-astral organization in which microtubule minus ends are linked to the sides of other microtubules. This raises the question of how branched-microtubule nucleation and dynein-mediated transport cooperate to organize the spindle poles...
November 22, 2023: Molecular Biology of the Cell
https://read.qxmd.com/read/37985763/vesicles-driven-by-dynein-and-kinesin-exhibit-directional-reversals-without-regulators
#12
JOURNAL ARTICLE
Ashwin I D'Souza, Rahul Grover, Gina A Monzon, Ludger Santen, Stefan Diez
Intracellular vesicular transport along cytoskeletal filaments ensures targeted cargo delivery. Such transport is rarely unidirectional but rather bidirectional, with frequent directional reversals owing to the simultaneous presence of opposite-polarity motors. So far, it has been unclear whether such complex motility pattern results from the sole mechanical interplay between opposite-polarity motors or requires regulators. Here, we demonstrate that a minimal system, comprising purified Dynein-Dynactin-BICD2 (DDB) and kinesin-3 (KIF16B) attached to large unilamellar vesicles, faithfully reproduces in vivo cargo motility, including runs, pauses, and reversals...
November 20, 2023: Nature Communications
https://read.qxmd.com/read/37984321/rzz-spindly-and-cenp-e-form-an-integrated-platform-to-recruit-dynein-to-the-kinetochore-corona
#13
JOURNAL ARTICLE
Verena Cmentowski, Giuseppe Ciossani, Ennio d'Amico, Sabine Wohlgemuth, Mikito Owa, Brian Dynlacht, Andrea Musacchio
Chromosome biorientation on the mitotic spindle is prerequisite to errorless genome inheritance. CENP-E (kinesin-7) and dynein-dynactin (DD), microtubule motors with opposite polarity, promote biorientation from the kinetochore corona, a polymeric structure whose assembly requires MPS1 kinase. The corona's building block consists of ROD, Zwilch, ZW10, and the DD adaptor Spindly (RZZS). How CENP-E and DD are scaffolded and mutually coordinated in the corona remains unclear. Here, we show that when corona assembly is prevented through MPS1 inhibition, CENP-E is absolutely required to retain RZZS at kinetochores...
November 20, 2023: EMBO Journal
https://read.qxmd.com/read/37949220/interaction-between-the-mitochondrial-adaptor-miro-and-the-motor-adaptor-trak
#14
JOURNAL ARTICLE
Elana E Baltrusaitis, Erika E Ravitch, Adam R Fenton, Tania Perez, Erika L F Holzbaur, Roberto Dominguez
MIRO (mitochondrial Rho GTPase) consists of two GTPase domains flanking two Ca2+ -binding EF-hand domains. A C-terminal transmembrane helix anchors MIRO to the outer mitochondrial membrane, where it functions as a general adaptor for the recruitment of cytoskeletal proteins that control mitochondrial dynamics. One protein recruited by MIRO is TRAK (trafficking kinesin-binding protein), which in turn recruits the microtubule-based motors kinesin-1 and dynein-dynactin. The mechanism by which MIRO interacts with TRAK on the mitochondrial membrane is not well understood...
November 8, 2023: Journal of Biological Chemistry
https://read.qxmd.com/read/37940657/nde1-promotes-lis1-mediated-activation-of-dynein
#15
JOURNAL ARTICLE
Yuanchang Zhao, Sena Oten, Ahmet Yildiz
Cytoplasmic dynein drives the motility and force generation functions towards the microtubule minus end. The assembly of dynein with dynactin and a cargo adaptor in an active transport complex is facilitated by Lis1 and Nde1/Ndel1. Recent studies proposed that Lis1 relieves dynein from its autoinhibited conformation, but the physiological function of Nde1/Ndel1 remains elusive. Here, we investigate how human Nde1 and Lis1 regulate the assembly and subsequent motility of mammalian dynein using in vitro reconstitution and single molecule imaging...
November 9, 2023: Nature Communications
https://read.qxmd.com/read/37909920/axonal-transport-of-autophagosomes-is-regulated-by-dynein-activators-jip3-jip4-and-arf-rab-gtpases
#16
JOURNAL ARTICLE
Sydney E Cason, Erika L F Holzbaur
Neuronal autophagosomes form and engulf cargos at presynaptic sites in the axon and are then transported to the soma to recycle their cargo. Autophagic vacuoles (AVs) mature en route via fusion with lysosomes to become degradatively competent organelles; transport is driven by the microtubule motor protein cytoplasmic dynein, with motor activity regulated by a sequential series of adaptors. Using lysate-based single-molecule motility assays and live-cell imaging in primary neurons, we show that JNK-interacting proteins 3 (JIP3) and 4 (JIP4) are activating adaptors for dynein that are regulated on autophagosomes and lysosomes by the small GTPases ARF6 and RAB10...
December 4, 2023: Journal of Cell Biology
https://read.qxmd.com/read/37872872/heatr5b-associates-with-dynein-dynactin-and-promotes-motility-of-ap1-bound-endosomal-membranes
#17
JOURNAL ARTICLE
Vanesa Madan, Lucas Albacete-Albacete, Li Jin, Pietro Scaturro, Joseph L Watson, Nadine Muschalik, Farida Begum, Jérôme Boulanger, Karl Bauer, Michael A Kiebler, Emmanuel Derivery, Simon L Bullock
The microtubule motor dynein mediates polarised trafficking of a wide variety of organelles, vesicles and macromolecules. These functions are dependent on the dynactin complex, which helps recruit cargoes to dynein's tail and activates motor movement. How the dynein-dynactin complex orchestrates trafficking of diverse cargoes is unclear. Here, we identify HEATR5B, an interactor of the adaptor protein-1 (AP1) clathrin adaptor complex, as a novel player in dynein-dynactin function. HEATR5B was recovered in a biochemical screen for proteins whose association with the dynein tail is augmented by dynactin...
October 24, 2023: EMBO Journal
https://read.qxmd.com/read/37871017/spatacsin-regulates-directionality-of-lysosome-trafficking-by-promoting-the-degradation-of-its-partner-ap5z1
#18
JOURNAL ARTICLE
Alexandre Pierga, Raphaël Matusiak, Margaux Cauhapé, Julien Branchu, Lydia Danglot, Maxime Boutry, Frédéric Darios
The endoplasmic reticulum (ER) forms contacts with the lysosomal compartment, regulating lysosome positioning and motility. The movements of lysosomes are controlled by the attachment of molecular motors to their surface. However, the molecular mechanisms by which ER controls lysosome dynamics are still elusive. Here, using mouse brain extracts and mouse embryonic fibroblasts, we demonstrate that spatacsin is an ER-resident protein regulating the formation of tubular lysosomes, which are highly dynamic. Screening for spatacsin partners required for tubular lysosome formation showed spatacsin to act by regulating protein degradation...
October 23, 2023: PLoS Biology
https://read.qxmd.com/read/37730751/conserved-roles-for-the-dynein-intermediate-chain-and-ndel1-in-assembly-and-activation-of-dynein
#19
JOURNAL ARTICLE
Kyoko Okada, Bharat R Iyer, Lindsay G Lammers, Pedro A Gutierrez, Wenzhe Li, Steven M Markus, Richard J McKenney
Processive transport by the microtubule motor cytoplasmic dynein requires the regulated assembly of a dynein-dynactin-adapter complex. Interactions between dynein and dynactin were initially ascribed to the dynein intermediate chain N-terminus and the dynactin subunit p150Glued . However, recent cryo-EM structures have not resolved this interaction, questioning its importance. The intermediate chain also interacts with Nde1/Ndel1, which compete with p150Glued for binding. We reveal that the intermediate chain N-terminus is a critical evolutionarily conserved hub that interacts with dynactin and Ndel1, the latter of which recruits LIS1 to drive complex assembly...
September 20, 2023: Nature Communications
https://read.qxmd.com/read/37647159/actin-and-microtubule-based-motors-contribute-to-clathrin-independent-endocytosis-in-yeast
#20
JOURNAL ARTICLE
Thaddeus K Woodard, Daniel J Rioux, Derek C Prosser
Most eukaryotic cells utilize clathrin-mediated endocytosis as well as multiple clathrin-independent pathways to internalize proteins and membranes. Although clathrin-mediated endocytosis has been studied extensively and many machinery proteins have been identified, clathrin-independent pathways remain poorly characterized by comparison. We previously identified the first known yeast clathrin-independent endocytic pathway, which relies on the actin-modulating GTPase Rho1, the formin Bni1 and unbranched actin filaments, but does not require the clathrin coat or core clathrin machinery proteins...
August 30, 2023: Molecular Biology of the Cell
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