2,495 research outputs found
Kinesin Light Chains Are Essential for Axonal Transport in Drosophila
Kinesin is a heterotetramer composed of two 115-kD heavy chains and two 58-kD light chains. The microtubule motor activity of kinesin is performed by the heavy chains, but the functions of the light chains are poorly understood. Mutations were generated in the Drosophila gene Kinesin light chain (Klc), and the phenotypic consequences of loss of Klc function were analyzed at the behavioral and cellular levels. Loss of Klc function results in progressive lethargy, crawling defects, and paralysis followed by death at the end of the second larval instar. Klc mutant axons contain large aggregates of membranous organelles in segmental nerve axons. These aggregates, or organelle jams (Hurd, D.D., and W.M. Saxton. 1996. Genetics. 144: 1075-1085), contain synaptic vesicle precursors as well as organelles that may be transported by kinesin, kinesin-like protein 68D, and cytoplasmic dynein, thus providing evidence that the loss of Klc function blocks multiple pathways of axonal transport. The similarity of the Klc and Khc ((Saxton et al. Cell 64:1093-1102; Hurd, D.D., and W.M. Saxton. 1996. Genetics 144: 1075-1085) mutant phenotypes indicates that KLC is essential for kinesin function, perhaps by tethering KHC to intracellular cargos or by activating the kinesin motor
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Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin.
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is a critical enzyme in the mevalonate pathway that regulates the biosynthesis of cholesterol as well as isoprenoids that mediate the membrane association of certain GTPases. Blockade of this enzyme by atorvastatin (AT) inhibits the destructive proinflammatory T helper cell (Th)1 response during experimental autoimmune encephalomyelitis and may be beneficial in the treatment of multiple sclerosis and other Th1-mediated autoimmune diseases. Here we present evidence linking specific isoprenoid intermediates of the mevalonate pathway to signaling pathways that regulate T cell autoimmunity. We demonstrate that the isoprenoid geranylgeranyl-pyrophosphate (GGPP) mediates proliferation, whereas both GGPP and its precursor, farnesyl-PP, regulate the Th1 differentiation of myelin-reactive T cells. Depletion of these isoprenoid intermediates in vivo via oral AT administration hindered these T cell responses by decreasing geranylgeranylated RhoA and farnesylated Ras at the plasma membrane. This was associated with reduced extracellular signal-regulated kinase (ERK) and p38 phosphorylation and DNA binding of their cotarget c-fos in response to T cell receptor activation. Inhibition of ERK and p38 mimicked the effects of AT and induced a Th2 cytokine shift. Thus, by connecting isoprenoid availability to regulation of Th1/Th2 fate, we have elucidated a mechanism by which AT may suppress Th1-mediated central nervous system autoimmune disease
Axonal stress kinase activation and tau misbehavior induced by kinesin-1 transport defects
Many neurodegenerative diseases exhibit axonal pathology, transport defects, and aberrant phosphorylation and aggregation of the microtubule binding protein tau. While mutant tau protein in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP17) causes aberrant microtubule binding and assembly of tau into filaments, the pathways leading to tau-mediated neurotoxicity in Alzheimer's disease and other neurodegenerative disorders in which tau protein is not genetically modified remain unknown. To test the hypothesis that axonal transport defects alone can cause pathological abnormalities in tau protein and neurodegeneration in the absence of mutant tau or amyloid β deposits, we induced transport defects by deletion of the kinesin light chain 1 (KLC1) subunit of the anterograde motor kinesin-1. We found that upon aging, early selective axonal transport defects in mice lacking the KLC1 protein (KLC1-/-) led to axonopathies with cytoskeletal disorganization and abnormal cargo accumulation. In addition, increased c-jun N-terminal stress kinase activation colocalized with aberrant tau in dystrophic axons. Surprisingly, swollen dystrophic axons exhibited abnormal tau hyperphosphorylation and accumulation. Thus, directly interfering with axonal transport is sufficient to activate stress kinase pathways initiating a biochemical cascade that drives normal tau protein into a pathological state found in a variety of neurodegenerative disorders including Alzheimer's disease.Fil: Falzone, Tomas Luis. Howard Hughes Medical Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Stokin, Gorazd B.. University Psychiatric Hospital; EsloveniaFil: Lillo, Concepción. University of California at San Diego; Estados UnidosFil: Rodrigues, Elizabeth M.. Howard Hughes Medical Institute; Estados UnidosFil: Westerman, Eileen L.. Howard Hughes Medical Institute; Estados UnidosFil: Williams, David S.. University of California at San Diego; Estados UnidosFil: Goldstein, Lawrence S. B.. Howard Hughes Medical Institute; Estados Unido
Kinesin-II is required for axonal transport of choline acetyltransferase in Drosophila
KLP64D and KLP68D are members of the kinesin-II family of proteins in Drosophila. Immunostaining for KLP68D and ribonucleic acid in situ hybridization for KLP64D demonstrated their preferential expression in cholinergic neurons. KLP68D was also found to accumulate in cholinergic neurons in axonal obstructions caused by the loss of kinesin light chain. Mutations in the KLP64D gene cause uncoordinated sluggish movement and death, and reduce transport of choline acetyltransferase from cell bodies to the synapse. The inviability of KLP64D mutations can be rescued by expression of mammalian KIF3A. Together, these data suggest that kinesin-II is required for the axonal transport of a soluble enzyme, choline acetyltransferase. in a specific subset of neurons in Drosophila. Furthermore, the data lead to the conclusion that the cargo transport requirements of different classes of neurons may lead to upregulation of specific pathways of axonal transport
The Genetics of Axonal Transport and Axonal Transport Disorders
Neurons are specialized cells with a complex architecture that includes elaborate dendritic branches and a long, narrow axon that extends from the cell body to the synaptic terminal. The organized transport of essential biological materials throughout the neuron is required to support its growth, function, and viability. In this review, we focus on insights that have emerged from the genetic analysis of long-distance axonal transport between the cell body and the synaptic terminal. We also discuss recent genetic evidence that supports the hypothesis that disruptions in axonal transport may cause or dramatically contribute to neurodegenerative diseases
The SAMI Galaxy Survey: energy sources of the turbulent velocity dispersion in spatially-resolved local star-forming galaxies
We investigate the energy sources of random turbulent motions of ionised gas
from H emission in eight local star-forming galaxies from the
Sydney-AAO Multi-object Integral field spectrograph (SAMI) Galaxy Survey. These
galaxies satisfy strict pure star-forming selection criteria to avoid
contamination from active galactic nuclei (AGN) or strong shocks/outflows.
Using the relatively high spatial and spectral resolution of SAMI, we find that
-- on sub-kpc scales our galaxies display a flat distribution of ionised gas
velocity dispersion as a function of star formation rate (SFR) surface density.
A major fraction of our SAMI galaxies shows higher velocity dispersion than
predictions by feedback-driven models, especially at the low SFR surface
density end. Our results suggest that additional sources beyond star formation
feedback contribute to driving random motions of the interstellar medium (ISM)
in star-forming galaxies. We speculate that gravity, galactic shear, and/or
magnetorotational instability (MRI) may be additional driving sources of
turbulence in these galaxies.Comment: 11 pages, 5 figures, 3 tables. Accepted by MNRA
Genetic Evidence for Selective Transport of Opsin and Arrestin by Kinesin-II in Mammalian Photoreceptors
AbstractTo test whether kinesin-II is important for transport in the mammalian photoreceptor cilium, and to identify its potential cargoes, we used Cre-loxP mutagenesis to remove the kinesin-II subunit, KIF3A, specifically from photoreceptors. Complete loss of KIF3A caused large accumulations of opsin, arrestin, and membranes within the photoreceptor inner segment, while the localization of α-transducin was unaffected. Other membrane, organelle, and transport markers, as well as opsin processing appeared normal. Loss of KIF3A ultimately caused apoptotic photoreceptor cell death similar to a known opsin transport mutant. The data suggest that kinesin-II is required to transport opsin and arrestin from the inner to the outer segment and that blocks in this transport pathway lead to photoreceptor cell death as found in retinitis pigmentosa
The SAMI Galaxy Survey: Asymmetry in Gas Kinematics and its links to Stellar Mass and Star Formation
We study the properties of kinematically disturbed galaxies in the SAMI
Galaxy Survey using a quantitative criterion, based on kinemetry (Krajnovic et
al.). The approach, similar to the application of kinemetry by Shapiro et al.
uses ionised gas kinematics, probed by H{\alpha} emission. By this method
23+/-7% of our 360-galaxy sub-sample of the SAMI Galaxy Survey are
kinematically asymmetric. Visual classifications agree with our kinemetric
results for 90% of asymmetric and 95% of normal galaxies. We find stellar mass
and kinematic asymmetry are inversely correlated and that kinematic asymmetry
is both more frequent and stronger in low-mass galaxies. This builds on
previous studies that found high fractions of kinematic asymmetry in low mass
galaxies using a variety of different methods. Concentration of star forma-
tion and kinematic disturbance are found to be correlated, confirming results
found in previous work. This effect is stronger for high mass galaxies (log(M*)
> 10) and indicates that kinematic disturbance is linked to centrally
concentrated star formation. Comparison of the inner (within 0.5Re) and outer
H{\alpha} equivalent widths of asymmetric and normal galaxies shows a small but
significant increase in inner equivalent width for asymmetric galaxies.Comment: 29 pages, 21 figure
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