Dr. Kenneth Kosik's research team at UC, Santa Barbara is interested in both the mechanisms of neuronal plasticity and its impairment in neurodegeneration. One facet of plasticity is the regulation of mRNA translocation and translation in dendrites. RNAs are not uniformly distributed in neurons, and a subset of mRNAs that extend into dendrites appear to position their translation products strategically to implement the morphological changes associated with activity-related changes in synapses.

Emerging work has attempted to link the translational regulation of these dendritic mRNAs to synaptic activity. The population of RNAs which segregate to the dendrite create a specialized locale possibly capable of implementing activity-related structural changes, including dendritic spine morphogenesis associated with enduring long-term potentiation. In dendrites, mRNAs are present as granules. They have observed translocation of RNA granules in neurons along microtubules and have engineered a nucleic acid-peptide complex capable of directly visualizing in living neurons the translocation of a 5' untranslated RNA sequence complexed to green fluoresecent protein.

Although synaptic activation can induce translation, how activation is coupled to translation of specific mRNAs is poorly understood. In contrast to local translation control, the delivery of new mRNAs in granules to the dendrite is a slower means of altering local protein composition. Using RNA sedimentation techniques they have isolated and characterized the RNA granule as a macromolecular control site where specific mRNAs are held in translational arrest until stimulated. Available projects are directed at identification of components within these granules, characterization of their interaction with microtubules, identification of specific proteins that interact with highly segregated neuronal RNAs, and the direct visualization of RNA transport. RNAs that sediment with a somewhat lower mass than granules are polysomes. In this fraction are a remarkable variety of microRNAs potentially capable of regulating translation locally.

The basis for experience-dependent modification of neural circuitry involves changes in both the efficacy of existing synapses and the patterning of new anatomical connections such as the elaboration of motile filopodial, new synapses and spines. Dr. Kosik’s lab cloned a protein called delta-catenin which is shared by both adherens junctions and synapses, two structures with an intertwined function and evolutionary history. Spine formation and filopodial elaboration must involve adhesive changes for neurite outgrowths to penetrate the neuropil and delimit portions of the newly extended membrane for a synapse of a defined composition. In the adherens junction, delta-catenin binds to classical cadherin as a neuronal specific Arm-repeat family member. Among the Arm-repeat family members, a sub-family that includes delta-catenin and the prototypical member, p120ctn, is distinguished by the presence of ten Arm-repeats and binding to the juxtamembrane region of the classical cadherins. Through its PDZ binding domain, delta-catenin is linked to the PDZ domains of several synaptic proteins. Delta-catenin is ideally positioned to bridge and coordinate activity-related changes in the synapse with changes in adhesion of the post-synaptic membrane.

In parallel to this work are studies directed at the underlying cellular mechanisms by which plasticity is lost in the course of neurodegeneration. The microtubule-associated protein tau is the focus of these studies and the projects focus principally on the changes that neurons undergo as tau becomes vulnerable to the formation of aggregates and inclusions. Most recently Dr. Kosik’s lab has completed a screen for compounds that are likely to inhibit the phosphorylation of tau, the likely first step in its transition toward the formation of intra-cellular aggregates.

Publications:

    2009

• Papagiannakopoulos T, Kosik KS. MicroRNA-124: Micromanager of Neurogenesis. Cell Stem Cell, 2009 May 8;4(5):375-76
• Xu N, Papagiannakopoulos T, Pan G, Thomson JA, Kosik KS. MicroRNA-145 Regulates OCT4, SOX2, and KLF4 and Represses Pluripotency in Human Embryonic Stem Cells. CELL. 2009 May 15;137
• Carrettiero DC, Hernandez I, Neveu P, Papagiannakopoulos T, Kosik KS. The cochaperone BAG2 sweeps paired helical filament- insoluble tau from the microtubule. J Neurosci. 2009 Feb 18;29(7):2151-61
• Kosik KS. Exploring the early origins of the synapse by comparative genomics. Biol Lett. 2009 Feb 23;5(1):108-11

   2008

• Mercer TR, Dinger ME, Mariani J, Kosik KS, Mehler MF, Mattick JS. Noncoding RNAs in Long-Term Memory Formation. Neuroscientist. 2008 Oct;14(5):434-45. Review
• Hikita ST, Kosik KS, Clegg DO, Bamdad C. MUC1* mediates the growth of human pluripotent stem cells. PLoS ONE. 2008 Oct 3;3(10):e3312
• Papagiannakopoulos T, Shapiro A, Kosik KS. MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res. 2008 Oct 1;68(19):8164-72
• Abu-Elneel K, Ochiishi T, Medina M, Remedi M, Gastaldi L, Caceres A, Kosik KS.A delta-catenin signaling pathway leading to dendritic protrusions.J Biol Chem. 2008 Nov 21;283(47):32781-91
• Kosik KS, Lopera F. Genetic testing must recognize impact of bad news on recipient. Nature. 2008 Jul 10;454(7201):158-9
• Ochiishi T, Futai K, Okamoto K, Kameyama K, Kosik KS. Regulation of AMPA receptor trafficking by delta-catenin. Mol Cell Neurosci. 2008 Dec;39(4):499-507
• Papagiannakopoulos T, Kosik KS. microRNAs: regulators of oncogenesis and stemness. BMC Med. 2008 Jun 24;6(1):15.
• Abu-Elneel K, Liu T, Gazzaniga FS, Nishimura Y, Wall DP, Geschwind DH, Lao K, Kosik KS. Heterogeneous dysregulation of microRNAs across the autism spectrum. Neurogenetics. 2008 Jul;9(3):153-61
• Sakarya O, Kosik KS, Oakley TH. Reconstructing ancestral genome content based on symmetrical best alignments and Dollo parsimony. Bioinformatics. 2008 24(5):606-612

   2007

• Glicksman MA, Cuny GD, Liu M, Dobson B, Auerbach K, Stein RL, Kosik KS. New approaches to the discovery of cdk5 inhibitors. Curr Alzheimer Res. 2007 Dec;4(5):547-9.
• Liu T, Papagiannakopoulos T, Puskar K, Qi S, Santiago F, Clay W, Lao K, Lee Y, Nelson SF, Kornblum HI, Doyle F, Petzold L, Shraiman B, Kosik KS. Detection of a MicroRNA Signal in an In Vivo Expression Set of mRNAs. PLoS ONE. 2007 Aug 29;2(8):e804.
• Kye MJ, Liu T, Levy SF, Xu NL, Groves BB, Bonneau R, Lao K, Kosik KS. Somatodendritic microRNAs identified by laser capture and multiplex RT-PCR. RNA. 2007 Aug;13(8):1224-34. Epub 2007 Jun 25.
• Sakarya O, Armstrong KA, Adamska M, Adamski M, Wang I-F, Tidor B, Degnan BM, Oakley TH, Kosik KS. A Post-synaptic Scaffold at the Origin of the Animal Kingdom. PLoS ONE. 2007 Jun 6;2:e506.
• Kumar P, Ambasta RK, Veereshwarayya V, Rosen KM, Kosik KS, Band H, Mestril R, Patterson C, Querfurth HW. CHIP and HSPs interact with {beta}-APP in a proteasome-dependent manner and influence A{beta} metabolism. Hum Mol Genet. 2007 Apr 1;16(7):848-64.

   2006

• Kosik KS. The neuronal microRNA system. Nat Rev Neurosci. 2006 Dec;7(12):911-20. Review.
• Kosik KS. Traveling the tau pathway: a personal account. J Alzheimers Dis. 2006;9(3 Suppl):251-6. Review.
• Donahue CP, Muratore C, Wu JY, Kosik KS, Wolfe MS. Stabilization of the tau exon 10 stem loop alters pre-mRNA splicing. J Biol Chem. 2006 Aug 18;281(33):23302-6. Epub 2006 Jun 16.
• Donahue CP, Kosik KS, Shors TJ. Growth hormone is produced within the hippocampus where it responds to age, sex, and stress. Proc Natl Acad Sci U S A; 103(15):6031-6.
• Krichevsky AM, Sonntag KC, Isacson O, Kosik KS. Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cells. 2006 Apr;24(4):857-64. Epub 2005 Dec 15.

   2005

• Kosik KS, Krichevsky AM. The Elegance of the MicroRNAs: A Neuronal Perspective. Neuron; 47(6):779-82. Review.
• Kosik KS, Krichevsky AM. A model for local regulation of translation near active synapses. Sci STKE; 2005(300):tr25.
• Monticelli S, Ansel KM, Xiao C, Socci ND, Krichevsky AM, Thai TH, Rajewsky N, Marks DS, Sander C, Rajewsky K, Rao A, Kosik KS. MicroRNA profiling of the murine hematopoietic system. Genome Biol.;6(8):R71.
• Ahn JS, Radhakrishnan ML, Mapelli M, Choi S, Tidor B, Cuny GD, Musacchio A, Yeh LA, Kosik KS. Defining Cdk5 ligand chemical space with small molecule inhibitors of tau phosphorylation. Chem Biol.;12(7):811-23.
• Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res.;65(14):6029-33.
• Rampal R, Arboleda-Velasquez JF, Nita-Lazar A, Kosik KS, Haltiwanger RS. Highly conserved O-fucose sites have distinct effects on Notch1 function. J Biol Chem.;280(37):32133-40.
• Arboleda-Velasquez JF, Rampal R, Fung E, Darland DC, Liu M, Martinez MC, Donahue CP, Navarro-Gonzalez MF, Libby P, D'Amore PA, Aikawa M, Haltiwanger RS, Kosik KS. CADASIL mutations impair Notch3 glycosylation by Fringe. Hum Mol Genet.;14(12):1631-9.
• Kosik KS, Donahue CP, Israely I, Liu X, Ochiishi T. Delta-catenin at the synaptic-adherens junction. Trends Cell Biol;15(3):172-8. Review.
• Kosik KS, Shimura H. Phosphorylated tau and the neurodegenerative foldopathies. Biochim Biophys Acta;1739(2-3):298-310. Review.