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Axonal transport

Sylvia Neumann, Romain Chassefeyre, George E Campbell, Sandra E Encalada
In axons, proper localization of proteins, vesicles, organelles, and other cargoes is accomplished by the highly regulated coordination of kinesins and dyneins, molecular motors that bind to cargoes and translocate them along microtubule (MT) tracks. Impairment of axonal transport is implicated in the pathogenesis of multiple neurodegenerative disorders including Alzheimer's and Huntington's diseases. To understand how MT-based cargo motility is regulated and to delineate its role in neurodegeneration, it is critical to analyze the detailed dynamics of moving cargoes inside axons...
October 22, 2016: Traffic
Shaul Yogev, Roshni Cooper, Richard Fetter, Mark Horowitz, Kang Shen
Axonal microtubule (MT) arrays are the major cytoskeleton substrate for cargo transport. How MT organization, i.e., polymer length, number, and minus-end spacing, is regulated and how it impinges on axonal transport are unclear. We describe a method for analyzing neuronal MT organization using light microscopy. This method circumvents the need for electron microscopy reconstructions and is compatible with live imaging of cargo transport and MT dynamics. Examination of a C. elegans motor neuron revealed how age, MT-associated proteins, and signaling pathways control MT length, minus-end spacing, and coverage...
October 19, 2016: Neuron
Ahmad Alodaib, Nara Sobreira, Wendy A Gold, Lisa G Riley, Nicole J Van Bergen, Meredith J Wilson, Bruce Bennetts, David R Thorburn, Corinne Boehm, John Christodoulou
Recent advances in next-generation sequencing strategies have led to the discovery of many novel disease genes. We describe here a non-consanguineous family with two affected boys presenting with early onset of severe axonal neuropathy, optic atrophy, intellectual disability, auditory neuropathy and chronic respiratory and gut disturbances. Whole-exome sequencing (WES) was performed on all family members and we identified compound heterozygous variants (c.[760C>A];[1528G>C];p.[(Gln254Lys);(Ala510Pro)] in the polyribonucleotide nucleotidyltransferase 1 (PNPT1) gene in both affected individuals...
October 19, 2016: European Journal of Human Genetics: EJHG
D Cartelli, G Cappelletti
Microtubules are dynamic structures normally associated to the cell division, during which they form the mitotic spindle, as well as to the initial phases of specification and polarization of various cell types, including neurons. Although microtubules could have a role in the death of many cells and tissues, the microtubule-based degenerative mechanisms have been poorly investigated; nevertheless, during the last two decades, many clues have been accumulated suggesting the importance of the microtubule system during neurodegeneration...
October 18, 2016: Molecular Neurobiology
Rose Gelineau-Morel, Marshall Lukacs, K Nicole Weaver, Robert B Hufnagel, Donald L Gilbert, Rolf W Stottmann
Whole exome sequencing continues to end the diagnostic odyssey for a number of patients and expands our knowledge of phenotypes associated with gene mutations. We describe an 11-year-old female patient with a constellation of symptoms including congenital cataracts, gut dysmotility, sensory neuropathy, and bifrontal polymicrogyria. Whole exome sequencing was performed and identified a de novo heterozygous missense mutation in the ATPase motor domain of cytoplasmic dynein heavy chain 1 (DYNC1H1), which is known to be involved in neuronal migration and retrograde axonal transport...
October 14, 2016: Genes
Christopher S Medina, Octavian Biris, Tomas L Falzone, Xiaowei Zhang, Amber J Zimmerman, Elaine L Bearer
Microtubule-based motors carry cargo back and forth between the synaptic region and the cell body. Defects in axonal transport result in peripheral neuropathies, some of which are caused by mutations in KIF5A, a gene encoding one of the heavy chain isoforms of conventional kinesin-1. Some mutations in KIF5A also cause severe central nervous system defects in humans. While transport dynamics in the peripheral nervous system have been well characterized experimentally, transport in the central nervous system is less experimentally accessible and until now not well described...
October 14, 2016: NeuroImage
Mansi R Khanna, Jane Kovalevich, Virginia M-Y Lee, John Q Trojanowski, Kurt R Brunden
A group of neurodegenerative diseases referred to as tauopathies are characterized by the presence of brain cells harboring inclusions of pathological species of the tau protein. These disorders include Alzheimer's disease and frontotemporal lobar degeneration due to tau pathology, including progressive supranuclear palsy, corticobasal degeneration, and Pick's disease. Tau is normally a microtubule (MT)-associated protein that appears to play an important role in ensuring proper axonal transport, but in tauopathies tau becomes hyperphosphorylated and disengages from MTs, with consequent misfolding and deposition into inclusions that mainly affect neurons but also glia...
October 2016: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
Yan Xu, Christopher C Quinn
Axonal branch formation and synaptogenesis are sequential events that are required for the establishment of neuronal connectivity. However, little is known about how the transition between these two events is regulated. Here, we report that the lin-4 microRNA can regulate the transition between branch formation and synaptogenesis in the PLM axon of C. elegans. The PLM axon grows a collateral branch during the early L1 stage and undergoes synaptogenesis during the late L1 stage. Loss of the lin-4 microRNA disrupts synaptogenesis during the late L1 stage, suggesting that lin-4 promotes synaptogenesis...
October 13, 2016: Developmental Biology
Yu Kobayashi, Jun Tohyama, Tomoyuki Akiyama, Shinichi Magara, Hideshi Kawashima, Noriyuki Akasaka, Mitsuko Nakashima, Hirotomo Saitsu, Naomichi Matsumoto
Cerebral folate deficiency due to folate receptor 1 gene (FOLR1) mutations is an autosomal recessive disorder resulting from a brain-specific folate transport defect. It is characterized by late infantile onset, severe psychomotor regression, epilepsy, and leukodystrophy. We describe a consanguineous girl exhibiting severe developmental regression, intractable epilepsy, polyneuropathy, and profound hypomyelination with cortical involvement. Magnetic resonance imaging showed cortical disturbances in addition to profound hypomyelination and cerebellar atrophy...
October 12, 2016: Brain & Development
Marco Bacigaluppi, Gianluca Luigi Russo, Luca Peruzzotti-Jametti, Silvia Rossi, Stefano Sandrone, Erica Butti, Roberta De Ceglia, Andrea Bergamaschi, Caterina Motta, Mattia Gallizioli, Valeria Studer, Emanuela Colombo, Cinthia Farina, Giancarlo Comi, Letterio Salvatore Politi, Luca Muzio, Claudia Villani, Roberto William Invernizzi, Dirk Matthias Hermann, Diego Centonze, Gianvito Martino
: Ischemic stroke is the leading cause of disability, but effective therapies are currently widely lacking. Recovery from stroke is very much dependent on the possibility to develop treatments able to both halt the neurodegenerative process as well as to foster adaptive tissue plasticity. Here we show that ischemic mice treated with neural precursor cell (NPC) transplantation had on neurophysiological analysis, early after treatment, reduced presynaptic release of glutamate within the ipsilesional corticospinal tract (CST), and an enhanced NMDA-mediated excitatory transmission in the contralesional CST...
October 12, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Lulu I T Korsak, Molly E Mitchell, Katherine A Shepard, Michael R Akins
RNA localization is a key mechanism in the regulation of protein expression. In neurons, this includes the axonal transport of select mRNAs based on the recognition of axonal localization motifs in these RNAs by RNA binding proteins. Bioinformatic analyses of axonal RNAs suggest that selective inclusion of such localization motifs in mature mRNAs is one mechanism controlling the composition of the axonal transcriptome. The subsequent translation of axonal transcripts in response to specific stimuli provides precise spatiotemporal control of the axonal proteome...
March 2016: Current Genetic Medicine Reports
Satoshi Sugita, Leland L Fleming, Caleb Wood, Sydney K Vaughan, Matheus P S M Gomes, Wallace Camargo, Ligia A Naves, Vania F Prado, Marco A M Prado, Cristina Guatimosim, Gregorio Valdez
BACKGROUND: Cholinergic dysfunction occurs during aging and in a variety of diseases, including amyotrophic lateral sclerosis (ALS). However, it remains unknown whether changes in cholinergic transmission contributes to age- and disease-related degeneration of the motor system. Here we investigated the effect of moderately increasing levels of synaptic acetylcholine (ACh) on the neuromuscular junction (NMJ), muscle fibers, and motor neurons during development and aging and in a mouse model for amyotrophic lateral sclerosis (ALS)...
2016: Skeletal Muscle
Guillermo López-Doménech, Nathalie F Higgs, Victoria Vaccaro, Hana Roš, I Lorena Arancibia-Cárcamo, Andrew F MacAskill, Josef T Kittler
Correct mitochondrial distribution is critical for satisfying local energy demands and calcium buffering requirements and supporting key cellular processes. The mitochondrially targeted proteins Miro1 and Miro2 are important components of the mitochondrial transport machinery, but their specific roles in neuronal development, maintenance, and survival remain poorly understood. Using mouse knockout strategies, we demonstrate that Miro1, as opposed to Miro2, is the primary regulator of mitochondrial transport in both axons and dendrites...
October 4, 2016: Cell Reports
K Ma, A Xu, S Cui, M-R Sun, Y-C Xue, J-H Wang
Major depression is a prevalent emotion disorder. Chronic stressful life in genetically susceptible individuals is presumably a major etiology that leads to neuron and synapse atrophy in the limbic system. Molecular mechanisms underlying the pathological changes remain elusive. Mice were treated by chronic unpredictable mild stress (CUMS) until they demonstrated depression-like behavior. GABA release in the medial prefrontal cortex was evaluated by cell electrophysiology and imaging. Molecular profiles related to GABA synthesis and uptake were investigated by the high-throughput sequencings of microRNAs and mRNAs as well as western blot analysis in this cortical area...
October 4, 2016: Translational Psychiatry
Mariana Oksdath, Alvaro F Nieto Guil, Diego Grassi, Lucas J Sosa, Santiago Quiroga
Three early signals of asymmetry have been described to occur in a single neurite of neurons at stage 2 of differentiation (before polarization) and shown to be essential for neuronal polarization: (i) accumulation of stable microtubules, (ii) enrichment of the plasma membrane with activatable IGF-1r, and (iii) polarized transport of the microtubular motor KIF5C. Here, we studied the possible relationship between these three phenomena. Our results show that the activatable (membrane-inserted) IGF-1r and stable microtubules accumulate in the same neurite of cells at stage 2...
October 3, 2016: Molecular Neurobiology
Ying Wang, Hua Jia, Wen-Yuan Li, Li-Xin Guan, Lingxiao Deng, Yan-Cui Liu, Gui-Bo Liu
The present study aimed to evaluate the molecular mechanisms underlying combinatorial bone marrow stromal cell (BMSC) transplantation and chondroitinase ABC (Ch-ABC) therapy in a model of acellular nerve allograft (ANA) repair of the sciatic nerve gap in rats. Sprague Dawley rats (n=24) were used as nerve donors and Wistar rats (n=48) were randomly divided into the following groups: Group I, Dulbecco's modified Eagle's medium (DMEM) control group (ANA treated with DMEM only); Group II, Ch-ABC group (ANA treated with Ch-ABC only); Group III, BMSC group (ANA seeded with BMSCs only); Group IV, Ch-ABC + BMSCs group (Ch-ABC treated ANA then seeded with BMSCs)...
October 2016: Experimental and Therapeutic Medicine
Tina Zimmermann, Floortje Remmers, Beat Lutz, Julia Leschik
Huntington's disease (HD) is characterized by fatal motoric failures induced by loss of striatal medium spiny neurons. Neuronal cell death has been linked to impaired expression and axonal transport of the neurotrophin BDNF (brain-derived neurotrophic factor). By transplanting embryonic stem cell-derived neural progenitors overexpressing BDNF, we combined cell replacement and BDNF supply as a potential HD therapy approach. Transplantation of purified neural progenitors was analyzed in a quinolinic acid (QA) chemical and two genetic HD mouse models (R6/2 and N171-82Q) on the basis of distinct behavioral parameters, including CatWalk gait analysis...
October 11, 2016: Stem Cell Reports
Vishruti Makani, Bin Zhang, Heeoon Han, Yuemang Yao, Pierrik Lassalas, Kevin Lou, Ian Paterson, Virginia M Y Lee, John Q Trojanowski, Carlo Ballatore, Amos B Smith, Kurt R Brunden
Neurodegenerative disorders referred to as tauopathies, which includes Alzheimer's disease (AD), are characterized by insoluble deposits of the tau protein within neuron cell bodies and dendritic processes in the brain. Tau is normally associated with microtubules (MTs) in axons, where it provides MT stabilization and may modulate axonal transport. However, tau becomes hyperphosphorylated and dissociates from MTs in tauopathies, with evidence of reduced MT stability and defective axonal transport. This has led to the hypothesis that MT-stabilizing drugs may have potential for the treatment of tauopathies...
September 29, 2016: Acta Neuropathologica Communications
Tong Wang, Sally Martin, Tam H Nguyen, Callista B Harper, Rachel S Gormal, Ramon Martínez-Mármol, Shanker Karunanithi, Elizabeth J Coulson, Nick R Glass, Justin J Cooper-White, Bruno van Swinderen, Frédéric A Meunier
Axonal retrograde transport of signalling endosomes from the nerve terminal to the soma underpins survival. As each signalling endosome carries a quantal amount of activated receptors, we hypothesized that it is the frequency of endosomes reaching the soma that determines the scale of the trophic signal. Here we show that upregulating synaptic activity markedly increased the flux of plasma membrane-derived retrograde endosomes (labelled using cholera toxin subunit-B: CTB) in hippocampal neurons cultured in microfluidic devices, and live Drosophila larval motor neurons...
2016: Nature Communications
Lyndsey E Collins-Praino, Frances Corrigan
A history of traumatic brain injury (TBI) is linked to an increased risk for the later development of dementia. This encompasses a variety of neurodegenerative diseases including Alzheimer's Disease (AD) and chronic traumatic encephalopathy (CTE), with AD linked to history of moderate-severe TBI and CTE to a history of repeated concussion. Of note, both AD and CTE are characterized by the abnormal accumulation of hyperphosphorylated tau aggregates, which are thought to play an important role in the development of neurodegeneration...
September 28, 2016: Brain, Behavior, and Immunity
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