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erika holzbaur

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https://www.readbyqxmd.com/read/28941293/cdk5-dependent-activation-of-dynein-in-the-axon-initial-segment-regulates-polarized-cargo-transport-in-neurons
#1
Eva Klinman, Mariko Tokito, Erika L F Holzbaur
The unique polarization of neurons depends on selective sorting of axonal and somatodendritic cargos to their correct compartments. Axodendritic sorting and filtering occurs within the axon initial segment (AIS). However, the underlying molecular mechanisms responsible for this filter are not well understood. Here, we show that local activation of the neuronal-specific kinase cyclin-dependent kinase 5 (CDK5) is required to maintain AIS integrity, as depletion or inhibition of CDK5 induces disordered microtubule polarity and loss of AIS cytoskeletal structure...
December 2017: Traffic
https://www.readbyqxmd.com/read/28938121/huntingtin-fibrils-poke-membranes
#2
COMMENT
Pedro Guedes-Dias, Erika L F Holzbaur
A hallmark of Huntington's disease is the presence of intracellular aggregates of mutant huntingtin, the pathological significance of which has long been debated. Using cryo-electron tomography, Bauerlein et al. reveal the fibrillary structure of huntingtin aggregates in situ and show that huntingtin fibrils interact with the endoplasmic reticulum, distorting its morphology and dynamics.
September 21, 2017: Cell
https://www.readbyqxmd.com/read/28855741/the-impact-of-cytoskeletal-organization-on-the-local-regulation-of-neuronal-transport
#3
REVIEW
Jeffrey J Nirschl, Amy E Ghiretti, Erika L F Holzbaur
Neurons are akin to modern cities in that both are dependent on robust transport mechanisms. Like the best mass transit systems, trafficking in neurons must be tailored to respond to local requirements. Neurons depend on both high-speed, long-distance transport and localized dynamics to correctly deliver cargoes and to tune synaptic responses. Here, we focus on the mechanisms that provide localized regulation of the transport machinery, including the cytoskeleton and molecular motors, to yield compartment-specific trafficking in the axon initial segment, axon terminal, dendrites and spines...
October 2017: Nature Reviews. Neuroscience
https://www.readbyqxmd.com/read/28720664/dynein-efficiently-navigates-the-dendritic-cytoskeleton-to-drive-the-retrograde-trafficking-of-bdnf-trkb-signaling-endosomes
#4
Swathi Ayloo, Pedro Guedes-Dias, Amy E Ghiretti, Erika L F Holzbaur
The efficient transport of cargoes within axons and dendrites is critical for neuronal function. Although we have a basic understanding of axonal transport, much less is known about transport in dendrites. We used an optogenetic approach to recruit motor proteins to cargo in real time within axons or dendrites in hippocampal neurons. Kinesin-1, a robust axonal motor, moves cargo less efficiently in dendrites. In contrast, cytoplasmic dynein efficiently navigates both axons and dendrites; in both compartments, dynamic microtubule plus ends enhance dynein-dependent transport...
September 15, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28533393/angular-measurements-of-the-dynein-ring-reveal-a-stepping-mechanism-dependent-on-a-flexible-stalk
#5
Lisa G Lippert, Tali Dadosh, Jodi A Hadden, Vishakha Karnawat, Benjamin T Diroll, Christopher B Murray, Erika L F Holzbaur, Klaus Schulten, Samara L Reck-Peterson, Yale E Goldman
The force-generating mechanism of dynein differs from the force-generating mechanisms of other cytoskeletal motors. To examine the structural dynamics of dynein's stepping mechanism in real time, we used polarized total internal reflection fluorescence microscopy with nanometer accuracy localization to track the orientation and position of single motors. By measuring the polarized emission of individual quantum nanorods coupled to the dynein ring, we determined the angular position of the ring and found that it rotates relative to the microtubule (MT) while walking...
June 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28265061/amyotrophic-lateral-sclerosis-linked-mutations-increase-the-viscosity-of-liquid-like-tdp-43-rnp-granules-in-neurons
#6
Pallavi P Gopal, Jeffrey J Nirschl, Eva Klinman, Erika L F Holzbaur
Ribonucleoprotein (RNP) granules are enriched in specific RNAs and RNA-binding proteins (RBPs) and mediate critical cellular processes. Purified RBPs form liquid droplets in vitro through liquid-liquid phase separation and liquid-like non-membrane-bound structures in cells. Mutations in the human RBPs TAR-DNA binding protein 43 (TDP-43) and RNA-binding protein FUS cause amyotrophic lateral sclerosis (ALS), but the biophysical properties of these proteins have not yet been studied in neurons. Here, we show that TDP-43 RNP granules in axons of rodent primary cortical neurons display liquid-like properties, including fusion with rapid relaxation to circular shape, shear stress-induced deformation, and rapid fluorescence recovery after photobleaching...
March 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27817978/activity-dependent-regulation-of-distinct-transport-and-cytoskeletal-remodeling-functions-of-the-dendritic-kinesin-kif21b
#7
Amy E Ghiretti, Edda Thies, Mariko K Tokito, Tianming Lin, E Michael Ostap, Matthias Kneussel, Erika L F Holzbaur
The dendritic arbor is subject to continual activity-dependent remodeling, requiring a balance between directed cargo trafficking and dynamic restructuring of the underlying microtubule tracks. How cytoskeletal components are able to dynamically regulate these processes to maintain this balance remains largely unknown. By combining single-molecule assays and live imaging in rat hippocampal neurons, we have identified the kinesin-4 KIF21B as a molecular regulator of activity-dependent trafficking and microtubule dynamicity in dendrites...
November 23, 2016: Neuron
https://www.readbyqxmd.com/read/27686185/dynamic-actin-cycling-through-mitochondrial-subpopulations-locally-regulates-the-fission-fusion-balance-within-mitochondrial-networks
#8
Andrew S Moore, Yvette C Wong, Cory L Simpson, Erika L F Holzbaur
Mitochondria form interconnected networks that dynamically remodel in response to cellular needs. Using live-cell imaging, we investigate the role of the actin cytoskeleton in regulating mitochondrial fission and fusion. We identify cycling of actin filaments onto and off of subsets of cellular mitochondria. The association of actin filaments with mitochondrial subpopulations is transient; actin quickly disassembles, then reassembles around a distinct subpopulation, efficiently cycling through all cellular mitochondria within 14 min...
September 30, 2016: Nature Communications
https://www.readbyqxmd.com/read/27484150/spatiotemporal-dynamics-of-autophagy-receptors-in-selective-mitophagy
#9
Andrew S Moore, Erika L F Holzbaur
Damaged mitochondria are turned over through a process of selective autophagy termed mitophagy. In mitophagy, unhealthy mitochondria are recognized and ubiquitinated by Parkinson disease-linked proteins PINK1 and PARK2. The subsequent recruitment of ubiquitin-binding autophagy receptors leads in turn to the sequestration of the damaged organelles into LC3-positive phagophores, precursors to autophagosomes. The precise identity of these receptors and how they are regulated has been the focus of considerable attention...
October 2, 2016: Autophagy
https://www.readbyqxmd.com/read/27365401/hook-adaptors-induce-unidirectional-processive-motility-by-enhancing-the-dynein-dynactin-interaction
#10
Mara A Olenick, Mariko Tokito, Malgorzata Boczkowska, Roberto Dominguez, Erika L F Holzbaur
Cytoplasmic dynein drives the majority of minus end-directed vesicular and organelle motility in the cell. However, it remains unclear how dynein is spatially and temporally regulated given the variety of cargo that must be properly localized to maintain cellular function. Recent work has suggested that adaptor proteins provide a mechanism for cargo-specific regulation of motors. Of particular interest, studies in fungal systems have implicated Hook proteins in the regulation of microtubule motors. Here we investigate the role of mammalian Hook proteins, Hook1 and Hook3, as potential motor adaptors...
August 26, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27251616/compartment-specific-regulation-of-autophagy-in-primary-neurons
#11
Sandra Maday, Erika L F Holzbaur
UNLABELLED: Autophagy is an essential degradative pathway that maintains neuronal homeostasis and prevents axon degeneration. Initial observations suggest that autophagy is spatially regulated in neurons, but how autophagy is regulated in distinct neuronal compartments is unclear. Using live-cell imaging in mouse hippocampal neurons, we establish the compartment-specific mechanisms of constitutive autophagy under basal conditions, as well as in response to stress induced by nutrient deprivation...
June 1, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27247382/dynamic-recruitment-and-activation-of-als-associated-tbk1-with-its-target-optineurin-are-required-for-efficient-mitophagy
#12
Andrew S Moore, Erika L F Holzbaur
Mitochondria play an essential role in maintaining cellular homeostasis. The removal of damaged or depolarized mitochondria occurs via mitophagy, in which damaged mitochondria are targeted for degradation via ubiquitination induced by PTEN-induced putative kinase 1 (PINK1) and Parkin. Mitophagy receptors, including optineurin (OPTN), nuclear dot 52 kDa protein (NDP52), and Tax1-binding protein 1 (TAX1BP1), are recruited to mitochondria via ubiquitin binding and mediate autophagic engulfment through their association with microtubule-associated protein light chain 3 (LC3)...
June 14, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27210554/the-dynamic-localization-of-cytoplasmic-dynein-in-neurons-is-driven-by-kinesin-1
#13
Alison E Twelvetrees, Stefano Pernigo, Anneri Sanger, Pedro Guedes-Dias, Giampietro Schiavo, Roberto A Steiner, Mark P Dodding, Erika L F Holzbaur
Cytoplasmic dynein, the major motor driving retrograde axonal transport, must be actively localized to axon terminals. This localization is critical as dynein powers essential retrograde trafficking events required for neuronal survival, such as neurotrophic signaling. Here, we demonstrate that the outward transport of dynein from soma to axon terminal is driven by direct interactions with the anterograde motor kinesin-1. In developing neurons, we find that dynein dynamically cycles between neurites, following kinesin-1 and accumulating in the nascent axon coincident with axon specification...
June 1, 2016: Neuron
https://www.readbyqxmd.com/read/27147049/methods-for-assessing-nuclear-rotation-and-nuclear-positioning-in-developing-skeletal-muscle-cells
#14
Meredith H Wilson, Matthew G Bray, Erika L F Holzbaur
Skeletal muscle cells are large syncytia, containing hundreds of nuclei positioned regularly along the length of the fiber. During development, nuclei are actively distributed throughout the myotube by the microtubule motor proteins, kinesin-1, and cytoplasmic dynein. Nuclear movement consists of translocation along the long axis of the cell concurrent with three-dimensional rotation of nuclei. In this chapter we describe methods for quantitatively assessing the speed of nuclear rotation in cultured myotubes using live-cell imaging techniques coupled with rigid body kinematic analyses...
2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27117409/the-kinesin-kif21b-regulates-microtubule-dynamics-and-is-essential-for-neuronal-morphology-synapse-function-and-learning-and-memory
#15
Mary Muhia, Edda Thies, Dorthe Labonté, Amy E Ghiretti, Kira V Gromova, Francesca Xompero, Corinna Lappe-Siefke, Irm Hermans-Borgmeyer, Dietmar Kuhl, Michaela Schweizer, Ora Ohana, Jürgen R Schwarz, Erika L F Holzbaur, Matthias Kneussel
The kinesin KIF21B is implicated in several human neurological disorders, including delayed cognitive development, yet it remains unclear how KIF21B dysfunction may contribute to pathology. One limitation is that relatively little is known about KIF21B-mediated physiological functions. Here, we generated Kif21b knockout mice and used cellular assays to investigate the relevance of KIF21B in neuronal and in vivo function. We show that KIF21B is a processive motor protein and identify an additional role for KIF21B in regulating microtubule dynamics...
May 3, 2016: Cell Reports
https://www.readbyqxmd.com/read/27061495/lipid-rafts-assemble-dynein-ensembles
#16
Jeffrey J Nirschl, Amy E Ghiretti, Erika L F Holzbaur
New work by Rai et al. identifies a novel mechanism regulating phagosome transport in cells: the clustering of dynein motors into lipid microdomains, leading to enhanced unidirectional motility. Clustering may be especially important for dynein, a motor that works most efficiently in teams.
May 2016: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/26972003/%C3%AE-tubulin-tyrosination-and-clip-170-phosphorylation-regulate-the-initiation-of-dynein-driven-transport-in-neurons
#17
Jeffrey J Nirschl, Maria M Magiera, Jacob E Lazarus, Carsten Janke, Erika L F Holzbaur
Motor-cargo recruitment to microtubules is often the rate-limiting step of intracellular transport, and defects in this recruitment can cause neurodegenerative disease. Here, we use in vitro reconstitution assays with single-molecule resolution, live-cell transport assays in primary neurons, computational image analysis, and computer simulations to investigate the factors regulating retrograde transport initiation in the distal axon. We find that phosphorylation of the cytoskeletal-organelle linker protein CLIP-170 and post-translational modifications of the microtubule track combine to precisely control the initiation of retrograde transport...
March 22, 2016: Cell Reports
https://www.readbyqxmd.com/read/26794526/comparative-analysis-of-axonal-transport-markers-in-primary-mammalian-neurons
#18
Eva Klinman, Erika L F Holzbaur
Axonal transport is important for neuronal development and the maintenance of effective neuronal function in mature cells. Observing the active transport of organelles and vesicles along the axons of living neurons has emerged as a valuable tool for probing the health of the neuron, and assessing changes associated with stress and neurodegenerative disease. Transport relies on two families of motor proteins: kinesins and dynein. Using these motors, a diverse set of cargos are transported toward the axon tip, the cell body, or anywhere in between...
2016: Methods in Cell Biology
https://www.readbyqxmd.com/read/26794519/live-cell-imaging-of-retrograde-transport-initiation-in-primary-neurons
#19
Jeffrey J Nirschl, Erika L F Holzbaur
Axonal transport is an essential function in neurons, as mutations in either motor proteins or their adaptors cause neurodegeneration. While some mutations cause a complete block in axonal transport, other mutations affect transport more subtly. This is especially true of mutations identified in human patients, many of which impair but do not block motor function in the cell. Dissecting the pathogenic mechanisms of these more subtle mutations requires assays that can tease apart the distinct phases of axonal transport, including transport initiation, sustained/regulated motility, and cargo-specific sorting or delivery...
2016: Methods in Cell Biology
https://www.readbyqxmd.com/read/26166569/stress-induced-cdk5-activation-disrupts-axonal-transport-via-lis1-ndel1-dynein
#20
Eva Klinman, Erika L F Holzbaur
Axonal transport is essential for neuronal function, and defects in transport are associated with multiple neurodegenerative diseases. Aberrant cyclin-dependent kinase 5 (CDK5) activity, driven by the stress-induced activator p25, also is observed in these diseases. Here we show that elevated CDK5 activity increases the frequency of nonprocessive events for a range of organelles, including lysosomes, autophagosomes, mitochondria, and signaling endosomes. Transport disruption induced by aberrant CDK5 activation depends on the Lis1/Ndel1 complex, which directly regulates dynein activity...
July 21, 2015: Cell Reports
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