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Gianina Ravenscroft, Nataliya Di Donato, Gabriele Hahn, Mark R Davis, Paul D Craven, Gemma Poke, Katherine R Neas, Teresa M Neuhann, William B Dobyns, Nigel G Laing
Autosomal dominantly inherited mutations of BICD2 are associated with congenital-onset spinal muscular atrophy characterised by lower limb predominance. A few cases have also showed upper motor neuron pathology, including presenting with features resembling hereditary spastic paraplegia. The age-of-onset for the published families is usually at birth but also included cases with childhood- and adult-onset disease. In this report we described two isolated probands that presented in utero with features associated with reduced fetal movements...
September 19, 2016: Neuromuscular Disorders: NMD
Vladislav Belyy, Max A Schlager, Helen Foster, Armando E Reimer, Andrew P Carter, Ahmet Yildiz
Kinesin and dynein motors transport intracellular cargos bidirectionally by pulling them in opposite directions along microtubules, through a process frequently described as a 'tug of war'. While kinesin produces 6 pN of force, mammalian dynein was found to be a surprisingly weak motor (0.5-1.5 pN) in vitro, suggesting that many dyneins are required to counteract the pull of a single kinesin. Mammalian dynein's association with dynactin and Bicaudal-D2 (BICD2) activates its processive motility, but it was unknown how this affects dynein's force output...
September 2016: Nature Cell Biology
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
Sabine Rudnik-Schöneborn, Florian Deden, Katja Eggermann, Thomas Eggermann, Dagmar Wieczorek, Bernd Sellhaus, Alfred Yamoah, Anand Goswami, Kristl G Claeys, Joachim Weis, Klaus Zerres
INTRODUCTION: Heterozygous BICD2 gene mutations cause a form of autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED). METHODS: We analyzed the BICD2 gene in a selected group of 25 index patients with neurogenic muscle atrophy. RESULTS: We identified 2 new BICD2 missense mutations, c.2515G>A, p.Gly839Arg, in a family with autosomal dominant inheritance, and c.2202G>T, p.Lys734Asn, as a de novo mutation in an isolated patient with similar phenotype...
September 2016: Muscle & Nerve
Richard J McKenney, Walter Huynh, Ronald D Vale, Minhajuddin Sirajuddin
Post-translational modifications (PTMs) of α/β-tubulin are believed to regulate interactions with microtubule-binding proteins. A well-characterized PTM involves in the removal and re-ligation of the C-terminal tyrosine on α-tubulin, but the purpose of this tyrosination-detyrosination cycle remains elusive. Here, we examined the processive motility of mammalian dynein complexed with dynactin and BicD2 (DDB) on tyrosinated versus detyrosinated microtubules. Motility was decreased ~fourfold on detyrosinated microtubules, constituting the largest effect of a tubulin PTM on motor function observed to date...
June 1, 2016: EMBO Journal
Andrew P Carter, Aristides G Diamant, Linas Urnavicius
Recent structures of the dynein motor in three different conformations reveal how it uses ATP hydrolysis to move along microtubules. Attention is now turning to how cytoplasmic dynein-1 and dynactin act together to carry cargos. Cryo-electron microscopy (cryo-EM) has revealed the structure of dynactin and how it binds dynein in the presence of a cargo adaptor protein Bicaudal-D2 (BICD2). Future questions will include how dynein-1 transports so many different cargos and how the 2.4MDa dynein/dynactin transport machine is regulated...
April 2016: Current Opinion in Structural Biology
Souichi Oe, Harukata Miki, Wataru Nishimura, Yasuko Noda
Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor critical for synaptic plasticity, neuronal development and neurite extension. BDNF mRNA is transported to dendrites and axons, where it is expressed locally. We previously reported that dendritic targeting elements in the BDNF 3' UTR are necessary for dendritic transport and interact with cytoplasmic polyadenylation element binding protein 1. Here, we demonstrated that the short 3' UTR directs local translation of BDNF and that locally synthesized BDNF exists in a novel compartment that does not co-localize with markers of endosomes, endoplasmic reticulum, Golgi or the trans-Golgi network...
March 26, 2016: Cell Structure and Function
Lilian A Martinez-Carrera, Brunhilde Wirth
Spinal muscular atrophies (SMAs) are characterized by degeneration of spinal motor neurons and muscle weakness. Autosomal recessive SMA is the most common form and is caused by homozygous deletions/mutations of the SMN1 gene. However, families with dominant inherited SMA have been reported, for most of them the causal gene remains unknown. Recently, we and others have identified heterozygous mutations in BICD2 as causative for autosomal dominant SMA, lower extremity-predominant, 2 (SMALED2) and hereditary spastic paraplegia (HSP)...
2015: Frontiers in Neuroscience
Yuxuan Guo, Yixian Zheng
Lamins, the type V nuclear intermediate filament proteins, are reported to function in both interphase and mitosis. For example, lamin deletion in various cell types can lead to an uneven distribution of the nuclear pore complexes (NPCs) in the interphase nuclear envelope, whereas deletion of B-type lamins results in spindle orientation defects in mitotic neural progenitor cells. How lamins regulate these functions is unknown. Using mouse cells deleted of different combinations or all lamins, we show that lamins are required to prevent the aggregation of NPCs in the nuclear envelope near centrosomes in late G2 and prophase...
October 1, 2015: Molecular Biology of the Cell
Dean Clift, Melina Schuh
Assembly of a bipolar microtubule spindle is essential for accurate chromosome segregation. In somatic cells, spindle bipolarity is determined by the presence of exactly two centrosomes. Remarkably, mammalian oocytes do not contain canonical centrosomes. This study reveals that mouse oocytes assemble a bipolar spindle by fragmenting multiple acentriolar microtubule-organizing centres (MTOCs) into a high number of small MTOCs to be able to then regroup and merge them into two equal spindle poles. We show that MTOCs are fragmented in a three-step process...
2015: Nature Communications
Alexandre D Baffet, Daniel J Hu, Richard B Vallee
Dynein recruitment to the nuclear envelope is required for pre-mitotic nucleus-centrosome interactions in nonneuronal cells and for apical nuclear migration in neural stem cells. In each case, dynein is recruited to the nuclear envelope (NE) specifically during G2 via two nuclear pore-mediated mechanisms involving RanBP2-BicD2 and Nup133-CENP-F. The mechanisms responsible for cell-cycle control of this behavior are unknown. We now find that Cdk1 serves as a direct master controller for NE dynein recruitment in neural stem cells and HeLa cells...
June 22, 2015: Developmental Cell
Mariko Matsuto, Fumi Kano, Masayuki Murata
Rab is a small GTP-binding protein family that regulates various pathways of vesicular transport. Although more than 60 Rab proteins are targeted to specific organelles in mammalian cells, the mechanisms underlying the specificity of Rab proteins for the respective organelles remain unknown. In this study, we reconstituted the Golgi targeting of Rab6A in streptolysin O (SLO)-permeabilized HeLa cells in a cytosol-dependent manner and investigated the biochemical requirements of targeting. Golgi-targeting assays identified Bicaudal-D (BICD)2, which is reportedly involved in the dynein-mediated transport of mRNAs during oogenesis and embryogenesis in Drosophila, as a cytosolic factor for the Golgi targeting of Rab6A in SLO-permeabilized HeLa cells...
October 2015: Biochimica et Biophysica Acta
Alexander P Drew, Danqing Zhu, Aditi Kidambi, Carolyn Ly, Shelisa Tey, Megan H Brewer, Azlina Ahmad-Annuar, Garth A Nicholson, Marina L Kennerson
Inherited peripheral neuropathies (IPNs) are a group of related diseases primarily affecting the peripheral motor and sensory neurons. They include the hereditary sensory neuropathies (HSN), hereditary motor neuropathies (HMN), and Charcot-Marie-Tooth disease (CMT). Using whole-exome sequencing (WES) to achieve a genetic diagnosis is particularly suited to IPNs, where over 80 genes are involved with weak genotype-phenotype correlations beyond the most common genes. We performed WES for 110 index patients with IPN where the genetic cause was undetermined after previous screening for mutations in common genes selected by phenotype and mode of inheritance...
March 2015: Molecular Genetics & Genomic Medicine
Kristien Peeters, Sven Bervoets, Teodora Chamova, Ivan Litvinenko, Els De Vriendt, Stoyan Bichev, Dahlia Kancheva, Vanyo Mitev, Marina Kennerson, Vincent Timmerman, Peter De Jonghe, Ivailo Tournev, John MacMillan, Albena Jordanova
The heavy chain 1 of cytoplasmic dynein (DYNC1H1) is responsible for movement of the motor complex along microtubules and recruitment of dynein components. Mutations in DYNC1H1 are associated with spinal muscular atrophy (SMA), hereditary motor and sensory neuropathy (HMSN), cortical malformations, or a combination of these. Combining linkage analysis and whole-exome sequencing, we identified a novel dominant defect in the DYNC1H1 tail domain (c.1792C>T, p.Arg598Cys) causing axonal HMSN. Mutation analysis of the tail region in 355 patients identified a de novo mutation (c...
March 2015: Human Mutation
Alexander M Rossor, Emily C Oates, Hannah K Salter, Yang Liu, Sinead M Murphy, Rebecca Schule, Michael A Gonzalez, Mariacristina Scoto, Rahul Phadke, Caroline A Sewry, Henry Houlden, Albena Jordanova, Iyailo Tournev, Teodora Chamova, Ivan Litvinenko, Stephan Zuchner, David N Herrmann, Julian Blake, Janet E Sowden, Gyuda Acsadi, Michael L Rodriguez, Manoj P Menezes, Nigel F Clarke, Michaela Auer Grumbach, Simon L Bullock, Francesco Muntoni, Mary M Reilly, Kathryn N North
Spinal muscular atrophy is a disorder of lower motor neurons, most commonly caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1 mutations are subclassified according to phenotype. Spinal muscular atrophy, lower extremity-predominant, is characterized by lower limb muscle weakness and wasting, associated with reduced numbers of lumbar motor neurons and is caused by mutations in DYNC1H1, which encodes a microtubule motor protein in the dynein-dynactin complex and one of its cargo adaptors, BICD2...
February 2015: Brain: a Journal of Neurology
David Asante, Nicola L Stevenson, David J Stephens
Cytoplasmic dynein-2 is the motor for retrograde intraflagellar transport (IFT), and mutations in dynein-2 are known to cause skeletal ciliopathies. Here, we define for the first time the composition of the human cytoplasmic dynein-2 complex. We show that the proteins encoded by the ciliopathy genes WDR34 and WDR60 are bona fide dynein-2 intermediate chains and are both required for dynein-2 function. In addition, we identify TCTEX1D2 as a unique dynein-2 light chain that is itself required for cilia function...
November 1, 2014: Journal of Cell Science
Max A Schlager, Ha Thi Hoang, Linas Urnavicius, Simon L Bullock, Andrew P Carter
Cytoplasmic dynein is an approximately 1.4 MDa multi-protein complex that transports many cellular cargoes towards the minus ends of microtubules. Several in vitro studies of mammalian dynein have suggested that individual motors are not robustly processive, raising questions about how dynein-associated cargoes can move over long distances in cells. Here, we report the production of a fully recombinant human dynein complex from a single baculovirus in insect cells. Individual complexes very rarely show directional movement in vitro...
September 1, 2014: EMBO Journal
Vera van Dis, Marijn Kuijpers, Elize D Haasdijk, Eva Teuling, Scott A Oakes, Casper C Hoogenraad, Dick Jaarsma
BACKGROUND: Fragmentation of stacked cisterns of the Golgi apparatus into dispersed smaller elements is a feature associated with degeneration of neurons in amyotrophic lateral sclerosis (ALS) and some other neurodegenerative disorders. However, the role of Golgi fragmentation in motor neuron degeneration is not well understood. RESULTS: Here we use a SOD1-ALS mouse model (low-copy Gurney G93A-SOD1 mouse) to show that motor neurons with Golgi fragmentation are retrogradely labeled by intramuscularly injected CTB (beta subunit of cholera toxin), indicating that Golgi fragmentation precedes neuromuscular denervation and axon retraction...
2014: Acta Neuropathologica Communications
Dick Jaarsma, Robert van den Berg, Phebe S Wulf, Susan van Erp, Nanda Keijzer, Max A Schlager, Esther de Graaff, Chris I De Zeeuw, R Jeroen Pasterkamp, Anna Akhmanova, Casper C Hoogenraad
Bicaudal-D (BICD) belongs to an evolutionary conserved family of dynein adaptor proteins. It was first described in Drosophila as an essential factor in fly oogenesis and embryogenesis. Missense mutations in a human BICD homologue, BICD2, have been linked to a dominant mild early onset form of spinal muscular atrophy. Here we further examine the in vivo function of BICD2 in Bicd2 knockout mice. BICD2-deficient mice develop disrupted laminar organization of cerebral cortex and the cerebellum, pointing to impaired radial neuronal migration...
2014: Nature Communications
Christopher Oldmeadow, David Mossman, Tiffany-Jane Evans, Elizabeth G Holliday, Paul A Tooney, Murray J Cairns, Jingqin Wu, Vaughan Carr, John R Attia, Rodney J Scott
Schizophrenia has a strong genetic basis, and genome-wide association studies (GWAS) have shown that effect sizes for individual genetic variants which increase disease risk are small, making detection and validation of true disease-associated risk variants extremely challenging. Specifically, we first identify genes with exons showing differential expression between cases and controls, indicating a splicing mechanism that may contribute to variation in disease risk and focus on those showing consistent differential expression between blood and brain tissue...
May 2014: Journal of Psychiatric Research
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