Microglial activation in an amyotrophic lateral sclerosis-like model caused by Ranbp2 loss and nucleocytoplasmic transport impairment in retinal ganglion neurons

  • Kyoung-in Cho
  • Dosuk Yoon
  • Minzhong Yu
  • Neal S. Peachey
  • Paulo A. FerreiraEmail author
Original Article


Nucleocytoplasmic transport is dysregulated in sporadic and familial amyotrophic lateral sclerosis (ALS) and retinal ganglion neurons (RGNs) are purportedly involved in ALS. The Ran-binding protein 2 (Ranbp2) controls rate-limiting steps of nucleocytoplasmic transport. Mice with Ranbp2 loss in Thy1+-motoneurons develop cardinal ALS-like motor traits, but the impairments in RGNs and the degree of dysfunctional consonance between RGNs and motoneurons caused by Ranbp2 loss are unknown. This will help to understand the role of nucleocytoplasmic transport in the differential vulnerability of neuronal cell types to ALS and to uncover non-motor endophenotypes with pathognomonic signs of ALS. Here, we ascertain Ranbp2’s function and endophenotypes in RGNs of an ALS-like mouse model lacking Ranbp2 in motoneurons and RGNs. Thy1+-RGNs lacking Ranbp2 shared with motoneurons the dysregulation of nucleocytoplasmic transport. RGN abnormalities were comprised morphologically by soma hypertrophy and optic nerve axonopathy and physiologically by a delay of the visual pathway’s evoked potentials. Whole-transcriptome analysis showed restricted transcriptional changes in optic nerves that were distinct from those found in sciatic nerves. Specifically, the level and nucleocytoplasmic partition of the anti-apoptotic and novel substrate of Ranbp2, Pttg1/securin, were dysregulated. Further, acetyl-CoA carboxylase 1, which modulates de novo synthesis of fatty acids and T-cell immunity, showed the highest up-regulation (35-fold). This effect was reflected by the activation of ramified CD11b+ and CD45+-microglia, increase of F4\80+-microglia and a shift from pseudopodial/lamellipodial to amoeboidal F4\80+-microglia intermingled between RGNs of naive mice. Further, there was the intracellular sequestration in RGNs of metalloproteinase-28, which regulates macrophage recruitment and polarization in inflammation. Hence, Ranbp2 genetic insults in RGNs and motoneurons trigger distinct paracrine signaling likely by the dysregulation of nucleocytoplasmic transport of neuronal-type selective substrates. Immune-modulators underpinning RGN-to-microglial signaling are regulated by Ranbp2, and this neuronal-glial system manifests endophenotypes that are likely useful in the prognosis and diagnosis of motoneuron diseases, such as ALS.


Ran-binding protein 2 (Ranbp2) Amyotrophic lateral sclerosis (ALS) Microglia Nucleocytoplasmic transport Metalloproteinase-28 (Mmp28) Acetyl-CoA carboxylase 1 (Acc1) Retinal ganglion neurons 



We thank Guoping Feng (MIT, Cambridge, MA) for SLICK-H mice, Ian Macara (Vanderbilt University, Nashville, TN) for the antibody against Ran-GTP, Sandra Stinnett for help with statistical analyses of RGN morphometry (Duke University, Durham, NC), Ying Hao for help with the processing of the specimens for transmission electron microscopy (Duke University, Durham, NC).

Author contributions

KC and PAF conceived and supervised the study; KC, NSP and PAF designed experiments; KC, MY and DY performed experiments; PAF provided new tools and reagents; KC, DY, NPS and PAF analyzed data; KC and PAF wrote the manuscript.


The study was funded by National Institutes of Health Grants GM083165, GM083165-03S1 and EY019492 to P.A.F. This work was also supported by a Core Grant (P30 EY025585) to Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and a Research Career Scientist Award to N.S.P. from the U.S. Department of Veterans Affairs.

Compliance with ethical standards

Conflict of interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. All authors consent for the publication of this study.

Availability of data and materials

The datasets supporting the conclusions of this article are available in the Sequence Reads Archives (SRA; of the National Center for Biotechnology Information (NCBI) with the accession number: SRP139153. Datasets of a total of ~ 17.4 billion bases of unprocessed RNA sequencing were deposited as FASTq files at the SRA. The project overview was deposited with the Bioproject accession number: PRJNA449172. The optic nerves of SLICK-H::Ranbp2+/+, SLICK-H::Ranbp2flox/flox and Tg-RBD2/3*-HA::SLICK-H::Ranbp2flox/flox have the respective biosamples accession numbers: SAMN08891694, SAMN08891693 and SAMN08891695. Other datasets and materials used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Supplementary material

18_2019_3078_MOESM1_ESM.pdf (1.1 mb)
Supplementary material 1 (PDF 1132 kb)


  1. 1.
    Zhang J, Ito H, Wate R, Ohnishi S, Nakano S, Kusaka H (2006) Altered distributions of nucleocytoplasmic transport-related proteins in the spinal cord of a mouse model of amyotrophic lateral sclerosis. Acta Neuropathol 112(6):673–680. CrossRefPubMedGoogle Scholar
  2. 2.
    Kinoshita Y, Ito H, Hirano A, Fujita K, Wate R, Nakamura M, Kaneko S, Nakano S, Kusaka H (2009) Nuclear contour irregularity and abnormal transporter protein distribution in anterior horn cells in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 68(11):1184–1192. CrossRefPubMedGoogle Scholar
  3. 3.
    Dormann D, Rodde R, Edbauer D, Bentmann E, Fischer I, Hruscha A, Than ME, Mackenzie IR, Capell A, Schmid B, Neumann M, Haass C (2010) ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J 29(16):2841–2857. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Xiao S, MacNair L, McGoldrick P, McKeever PM, McLean JR, Zhang M, Keith J, Zinman L, Rogaeva E, Robertson J (2015) Isoform-specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis. Ann Neurol 78(4):568–583. CrossRefPubMedGoogle Scholar
  5. 5.
    Nagara Y, Tateishi T, Yamasaki R, Hayashi S, Kawamura M, Kikuchi H, Iinuma KM, Tanaka M, Iwaki T, Matsushita T, Ohyagi Y, Kira J (2013) Impaired cytoplasmic-nuclear transport of hypoxia-inducible factor-1alpha in amyotrophic lateral sclerosis. Brain Pathol 23(5):534–546. CrossRefPubMedGoogle Scholar
  6. 6.
    Ward ME, Taubes A, Chen R, Miller BL, Sephton CF, Gelfand JM, Minami S, Boscardin J, Martens LH, Seeley WW, Yu G, Herz J, Filiano AJ, Arrant AE, Roberson ED, Kraft TW, Farese RV Jr, Green A, Gan L (2014) Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD. J Exp Med 211(10):1937–1945. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, Badders N, Valentine M, Miller BL, Wong PC, Petrucelli L, Kim HJ, Gao FB, Taylor JP (2015) GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525(7567):129–133. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD (2015) The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525(7567):56–61. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Shang J, Yamashita T, Nakano Y, Morihara R, Li X, Feng T, Liu X, Huang Y, Fukui Y, Hishikawa N, Ohta Y, Abe K (2017) Aberrant distributions of nuclear pore complex proteins in ALS mice and ALS patients. Neuroscience 350:158–168. CrossRefPubMedGoogle Scholar
  10. 10.
    Ferreira PA (2019) The coming-of-age of nucleocytoplasmic transport in motor neuron disease and neurodegeneration. Cell Mol Life Sci. (in press) CrossRefPubMedGoogle Scholar
  11. 11.
    Woerner AC, Frottin F, Hornburg D, Feng LR, Meissner F, Patra M, Tatzelt J, Mann M, Winklhofer KF, Hartl FU, Hipp MS (2016) Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA. Science 351(6269):173–176. CrossRefPubMedGoogle Scholar
  12. 12.
    Grima JC, Daigle JG, Arbez N, Cunningham KC, Zhang K, Ochaba J, Geater C, Morozko E, Stocksdale J, Glatzer JC, Pham JT, Ahmed I, Peng Q, Wadhwa H, Pletnikova O, Troncoso JC, Duan W, Snyder SH, Ranum LPW, Thompson LM, Lloyd TE, Ross CA, Rothstein JD (2017) Mutant huntingtin disrupts the nuclear pore complex. Neuron 94(1):93–107 e106. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Gasset-Rosa F, Chillon-Marinas C, Goginashvili A, Atwal RS, Artates JW, Tabet R, Wheeler VC, Bang AG, Cleveland DW, Lagier-Tourenne C (2017) Polyglutamine-expanded huntingtin exacerbates age-related disruption of nuclear integrity and nucleocytoplasmic transport. Neuron 94(1):48–57 e44. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Eftekharzadeh B, Daigle JG, Kapinos LE, Coyne A, Schiantarelli J, Carlomagno Y, Cook C, Miller SJ, Dujardin S, Amaral AS, Grima JC, Bennett RE, Tepper K, DeTure M, Vanderburgh CR, Corjuc BT, DeVos SL, Gonzalez JA, Chew J, Vidensky S, Gage FH, Mertens J, Troncoso J, Mandelkow E, Salvatella X, Lim RYH, Petrucelli L, Wegmann S, Rothstein JD, Hyman BT (2018) Tau protein disrupts nucleocytoplasmic transport in Alzheimer’s disease. Neuron 99(5):925–940 e927. CrossRefPubMedGoogle Scholar
  15. 15.
    Cho KI, Orry A, Park SE, Ferreira PA (2015) Targeting the cyclophilin domain of Ran-binding protein 2 (Ranbp2) with novel small molecules to control the proteostasis of STAT3, hnRNPA2B1 and M-Opsin. ACS Chem Neurosci 6(8):1476–1485. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Jovicic A, Mertens J, Boeynaems S, Bogaert E, Chai N, Yamada SB, Paul JW 3rd, Sun S, Herdy JR, Bieri G, Kramer NJ, Gage FH, Van Den Bosch L, Robberecht W, Gitler AD (2015) Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci 18(9):1226–1229. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Boeynaems S, Bogaert E, Michiels E, Gijselinck I, Sieben A, Jovicic A, De Baets G, Scheveneels W, Steyaert J, Cuijt I, Verstrepen KJ, Callaerts P, Rousseau F, Schymkowitz J, Cruts M, Van Broeckhoven C, Van Damme P, Gitler AD, Robberecht W, Van Den Bosch L (2016) Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD. Sci Rep 6:20877. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Delphin C, Guan T, Melchior F, Gerace L (1997) RanGTP targets p97 to RanBP2, a filamentous protein localized at the cytoplasmic periphery of the nuclear pore complex. Mol Biol Cell 8(12):2379–2390CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Wu J, Matunis MJ, Kraemer D, Blobel G, Coutavas E (1995) Nup358, a cytoplasmically exposed nucleoporin with peptide repeats, Ran-GTP binding sites, zinc fingers, a cyclophilin A homologous domain, and a leucine-rich region. J Biol Chem 270(23):14209–14213CrossRefPubMedGoogle Scholar
  20. 20.
    Singh BB, Patel HH, Roepman R, Schick D, Ferreira PA (1999) The zinc finger cluster domain of RanBP2 is a specific docking site for the nuclear export factor, exportin-1. J Biol Chem 274(52):37370–37378CrossRefPubMedGoogle Scholar
  21. 21.
    Culjkovic-Kraljacic B, Baguet A, Volpon L, Amri A, Borden KL (2012) The oncogene eIF4E reprograms the nuclear pore complex to promote mRNA export and oncogenic transformation. Cell Rep 2(2):207–215. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Mahadevan K, Zhang H, Akef A, Cui XA, Gueroussov S, Cenik C, Roth FP, Palazzo AF (2013) RanBP2/Nup358 potentiates the translation of a subset of mRNAs encoding secretory proteins. PLoS Biol 11(4):e1001545. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Vetter IR, Nowak C, Nishimoto T, Kuhlmann J, Wittinghofer A (1999) Structure of a Ran-binding domain complexed with Ran bound to a GTP analogue: implications for nuclear transport. Nature 398(6722):39–46CrossRefPubMedGoogle Scholar
  24. 24.
    Villa Braslavsky CI, Nowak C, Gorlich D, Wittinghofer A, Kuhlmann J (2000) Different structural and kinetic requirements for the interaction of Ran with the Ran-binding domains from RanBP2 and importin-beta. Biochemistry (Mosc) 39(38):11629–11639CrossRefGoogle Scholar
  25. 25.
    Ritterhoff T, Das H, Hofhaus G, Schroder RR, Flotho A, Melchior F (2016) The RanBP2/RanGAP1*SUMO1/Ubc9 SUMO E3 ligase is a disassembly machine for Crm1-dependent nuclear export complexes. Nat Commun 7:11482. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Mahajan R, Gerace L, Melchior F (1998) Molecular characterization of the SUMO-1 modification of RanGAP1 and its role in nuclear envelope association. J Cell Biol 140(2):259–270CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Saitoh H, Pu R, Cavenagh M, Dasso M (1997) RanBP2 associates with Ubc9p and a modified form of RanGAP1. Proc Natl Acad Sci USA 94(8):3736–3741CrossRefPubMedGoogle Scholar
  28. 28.
    Matunis MJ, Coutavas E, Blobel G (1996) A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex. J Cell Biol 135(6 Pt 1):1457–1470CrossRefPubMedGoogle Scholar
  29. 29.
    Walther TC, Pickersgill HS, Cordes VC, Goldberg MW, Allen TD, Mattaj IW, Fornerod M (2002) The cytoplasmic filaments of the nuclear pore complex are dispensable for selective nuclear protein import. J Cell Biol 158(1):63–77CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Hamada M, Haeger A, Jeganathan KB, van Ree JH, Malureanu L, Walde S, Joseph J, Kehlenbach RH, van Deursen JM (2011) Ran-dependent docking of importin-beta to RanBP2/Nup358 filaments is essential for protein import and cell viability. J Cell Biol 194(4):597–612. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Walde S, Thakar K, Hutten S, Spillner C, Nath A, Rothbauer U, Wiemann S, Kehlenbach RH (2012) The nucleoporin Nup358/RanBP2 promotes nuclear import in a cargo- and transport receptor-specific manner. Traffic 13(2):218–233. CrossRefPubMedGoogle Scholar
  32. 32.
    Patil H, Saha A, Senda E, Cho KI, Haque M, Yu M, Qiu S, Yoon D, Hao Y, Peachey NS, Ferreira PA (2014) Selective impairment of a subset of Ran-GTP-binding domains of Ran-binding protein 2 (Ranbp2) suffices to recapitulate the degeneration of the retinal pigment epithelium (RPE) triggered by Ranbp2 ablation. J Biol Chem 298:29767–29789. CrossRefGoogle Scholar
  33. 33.
    Cho KI, Patil H, Senda E, Wang J, Yi H, Qiu S, Yoon D, Yu M, Orry A, Peachey NS, Ferreira PA (2014) Differential loss of prolyl isomerase or chaperone activity of Ran-binding protein 2 (Ranbp2) unveils distinct physiological roles of its cyclophilin domain in proteostasis. J Biol Chem 289(8):4600–4625. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Cho KI, Yoon D, Qiu S, Danziger Z, Grill WM, Wetsel WC, Ferreira PA (2017) Loss of Ranbp2 in motoneurons causes disruption of nucleocytoplasmic and chemokine signaling, proteostasis of hnRNPH3 and Mmp28, and development of amyotrophic lateral sclerosis-like syndromes. Dis Model Mech 10(5):559–579. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Mavlyutov TA, Cai Y, Ferreira PA (2002) Identification of RanBP2- and kinesin-mediated transport pathways with restricted neuronal and subcellular localization. Traffic 3(9):630–640CrossRefPubMedGoogle Scholar
  36. 36.
    Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP (2013) Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495(7442):467–473. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H (2010) Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465(7295):223–226. CrossRefPubMedGoogle Scholar
  38. 38.
    Del Bo R, Tiloca C, Pensato V, Corrado L, Ratti A, Ticozzi N, Corti S, Castellotti B, Mazzini L, Soraru G, Cereda C, D’Alfonso S, Gellera C, Comi GP, Silani V, Consortium S (2011) Novel optineurin mutations in patients with familial and sporadic amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 82(11):1239–1243. CrossRefPubMedGoogle Scholar
  39. 39.
    Aung T, Rezaie T, Okada K, Viswanathan AC, Child AH, Brice G, Bhattacharya SS, Lehmann OJ, Sarfarazi M, Hitchings RA (2005) Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene. Invest Ophthalmol Vis Sci 46(8):2816–2822. CrossRefPubMedGoogle Scholar
  40. 40.
    Rezaie T, Child A, Hitchings R, Brice G, Miller L, Coca-Prados M, Heon E, Krupin T, Ritch R, Kreutzer D, Crick RP, Sarfarazi M (2002) Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 295(5557):1077–1079. CrossRefPubMedGoogle Scholar
  41. 41.
    De Marco N, Buono M, Troise F, Diez-Roux G (2006) Optineurin increases cell survival and translocates to the nucleus in a Rab8-dependent manner upon an apoptotic stimulus. J Biol Chem 281(23):16147–16156. CrossRefPubMedGoogle Scholar
  42. 42.
    Munte TF, Troger MC, Nusser I, Wieringa BM, Johannes S, Matzke M, Dengler R (1998) Alteration of early components of the visual evoked potential in amyotrophic lateral sclerosis. J Neurol 245(4):206–210CrossRefPubMedGoogle Scholar
  43. 43.
    Ringelstein M, Albrecht P, Sudmeyer M, Harmel J, Muller AK, Keser N, Finis D, Ferrea S, Guthoff R, Schnitzler A, Hartung HP, Methner A, Aktas O (2014) Subtle retinal pathology in amyotrophic lateral sclerosis. Ann Clin Transl Neurol 1(4):290–297. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Hubers A, Muller HP, Dreyhaupt J, Bohm K, Lauda F, Tumani H, Kassubek J, Ludolph AC, Pinkhardt EH (2016) Retinal involvement in amyotrophic lateral sclerosis: a study with optical coherence tomography and diffusion tensor imaging. J Neural Transm (Vienna) 123(3):281–287. CrossRefGoogle Scholar
  45. 45.
    Simonett JM, Huang R, Siddique N, Farsiu S, Siddique T, Volpe NJ, Fawzi AA (2016) Macular sub-layer thinning and association with pulmonary function tests in amyotrophic lateral sclerosis. Sci Rep 6:29187. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Nijssen J, Comley LH, Hedlund E (2017) Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis. Acta Neuropathol 133(6):863–885. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Young P, Qiu L, Wang D, Zhao S, Gross J, Feng G (2008) Single-neuron labeling with inducible Cre-mediated knockout in transgenic mice. Nat Neurosci 11(6):721–728. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Cho KI, Haque M, Wang J, Yu M, Hao Y, Qiu S, Pillai IC, Peachey NS, Ferreira PA (2013) Distinct and atypical intrinsic and extrinsic cell death pathways between photoreceptor cell types upon specific ablation of Ranbp2 in cone photoreceptors. PLoS Genet 9(6):e1003555. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Dawlaty MM, Malureanu L, Jeganathan KB, Kao E, Sustmann C, Tahk S, Shuai K, Grosschedl R, van Deursen JM (2008) Resolution of sister centromeres requires RanBP2-mediated SUMOylation of topoisomerase IIalpha. Cell 133(1):103–115CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Yu M, Sturgill-Short G, Ganapathy P, Tawfik A, Peachey NS, Smith SB (2012) Age-related changes in visual function in cystathionine-beta-synthase mutant mice, a model of hyperhomocysteinemia. Exp Eye Res 96(1):124–131. CrossRefPubMedGoogle Scholar
  51. 51.
    Richards SA, Lounsbury KM, Macara IG (1995) The C terminus of the nuclear RAN/TC4 GTPase stabilizes the GDP-bound state and mediates interactions with RCC1, RAN-GAP, and HTF9A/RANBP1. J Biol Chem 270(24):14405–14411CrossRefPubMedGoogle Scholar
  52. 52.
    Chi NC, Adam EJ, Adam SA (1995) Sequence and characterization of cytoplasmic nuclear protein import factor p97. J Cell Biol 130(2):265–274CrossRefPubMedGoogle Scholar
  53. 53.
    Cho KI, Searle K, Webb M, Yi H, Ferreira PA (2012) Ranbp2 haploinsufficiency mediates distinct cellular and biochemical phenotypes in brain and retinal dopaminergic and glia cells elicited by the Parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Cell Mol Life Sci 69(20):3511–3527. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Cho KI, Yi H, Tserentsoodol N, Searle K, Ferreira PA (2010) Neuroprotection resulting from insufficiency of RANBP2 is associated with the modulation of protein and lipid homeostasis of functionally diverse but linked pathways in response to oxidative stress. Dis Model Mech 3(9–10):595–604. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Cho KI, Yi H, Yeh A, Tserentsoodol N, Cuadrado L, Searle K, Hao Y, Ferreira PA (2009) Haploinsufficiency of RanBP2 is neuroprotective against light-elicited and age-dependent degeneration of photoreceptor neurons. Cell Death Differ 16(2):287–297. CrossRefPubMedGoogle Scholar
  56. 56.
    Trapnell C, Roberts A, Goff L, Pertea G, Kim D, Kelley DR, Pimentel H, Salzberg SL, Rinn JL, Pachter L (2012) Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc 7(3):562–578. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Chen L, Hambright WS, Na R, Ran Q (2015) Ablation of the ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis. J Biol Chem 290(47):28097–28106. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Altmann C, Vasic V, Hardt S, Heidler J, Haussler A, Wittig I, Schmidt MHH, Tegeder I (2016) Progranulin promotes peripheral nerve regeneration and reinnervation: role of notch signaling. Mol Neurodegener 11(1):69. CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Lebrun-Julien F, Suter U (2015) Combined HDAC1 and HDAC2 depletion promotes retinal ganglion cell survival after injury through reduction of p53 target gene expression. ASN Neuro 7(3):1759091415593066. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Peachey NS, Roveri L, Messing A, McCall MA (1997) Functional consequences of oncogene-induced horizontal cell degeneration in the retinas of transgenic mice. Vis Neurosci 14(4):627–632CrossRefPubMedGoogle Scholar
  61. 61.
    Ridder WH 3rd, Nusinowitz S (2006) The visual evoked potential in the mouse—origins and response characteristics. Vision Res 46(6–7):902–913. CrossRefPubMedGoogle Scholar
  62. 62.
    Barnard AR, Charbel Issa P, Perganta G, Williams PA, Davies VJ, Sekaran S, Votruba M, MacLaren RE (2011) Specific deficits in visual electrophysiology in a mouse model of dominant optic atrophy. Exp Eye Res 93(5):771–777. CrossRefPubMedGoogle Scholar
  63. 63.
    O’Neill JH, Jacobs JM, Gilliatt RW, Baba M (1984) Changes in the compact myelin of single internodes during axonal atrophy. Acta Neuropathol 63(4):313–318CrossRefPubMedGoogle Scholar
  64. 64.
    Soma S, Shimegi S, Suematsu N, Sato H (2013) Cholinergic modulation of response gain in the rat primary visual cortex. Sci Rep 3:1138. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Kirsh O, Seeler JS, Pichler A, Gast A, Muller S, Miska E, Mathieu M, Harel-Bellan A, Kouzarides T, Melchior F, Dejean A (2002) The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase. EMBO J 21(11):2682–2691. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Scognamiglio A, Nebbioso A, Manzo F, Valente S, Mai A, Altucci L (2008) HDAC-class II specific inhibition involves HDAC proteasome-dependent degradation mediated by RANBP2. Biochim Biophys Acta 1783(10):2030–2038. CrossRefPubMedGoogle Scholar
  67. 67.
    Tong Y, Eigler T (2009) Transcriptional targets for pituitary tumor-transforming gene-1. J Mol Endocrinol 43(5):179–185. CrossRefPubMedGoogle Scholar
  68. 68.
    Waite M, Wakil SJ (1962) Studies on the mechanism of fatty acid synthesis. XII. Acetyl coenzyme A carboxylase. J Biol Chem 237:2750–2757PubMedGoogle Scholar
  69. 69.
    Brownsey RW, Boone AN, Elliott JE, Kulpa JE, Lee WM (2006) Regulation of acetyl-CoA carboxylase. Biochem Soc Trans 34(Pt 2):223–227. CrossRefPubMedGoogle Scholar
  70. 70.
    Lee J, Walsh MC, Hoehn KL, James DE, Wherry EJ, Choi Y (2014) Regulator of fatty acid metabolism, acetyl coenzyme a carboxylase 1, controls T cell immunity. J Immunol 192(7):3190–3199. CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S, Harmrolfs K, Sandouk A, Hesse C, Castro CN, Bahre H, Tschirner SK, Gorinski N, Gohmert M, Mayer CT, Huehn J, Ponimaskin E, Abraham WR, Muller R, Lochner M, Sparwasser T (2014) De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med 20(11):1327–1333. CrossRefPubMedGoogle Scholar
  72. 72.
    Dombrowski Y, O’Hagan T, Dittmer M, Penalva R, Mayoral SR, Bankhead P, Fleville S, Eleftheriadis G, Zhao C, Naughton M, Hassan R, Moffat J, Falconer J, Boyd A, Hamilton P, Allen IV, Kissenpfennig A, Moynagh PN, Evergren E, Perbal B, Williams AC, Ingram RJ, Chan JR, Franklin RJM, Fitzgerald DC (2017) Regulatory T cells promote myelin regeneration in the central nervous system. Nat Neurosci 20(5):674–680. CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91(2):461–553. CrossRefPubMedGoogle Scholar
  74. 74.
    Prinz M, Priller J (2014) Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 15(5):300–312. CrossRefPubMedGoogle Scholar
  75. 75.
    Zhao L, Zabel MK, Wang X, Ma W, Shah P, Fariss RN, Qian H, Parkhurst CN, Gan WB, Wong WT (2015) Microglial phagocytosis of living photoreceptors contributes to inherited retinal degeneration. EMBO Mol Med 7(9):1179–1197. CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Manicone AM, Birkland TP, Lin M, Betsuyaku T, van Rooijen N, Lohi J, Keski-Oja J, Wang Y, Skerrett SJ, Parks WC (2009) Epilysin (MMP-28) restrains early macrophage recruitment in Pseudomonas aeruginosa pneumonia. J Immunol 182(6):3866–3876. CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Gharib SA, Johnston LK, Huizar I, Birkland TP, Hanson J, Wang Y, Parks WC, Manicone AM (2014) MMP28 promotes macrophage polarization toward M2 cells and augments pulmonary fibrosis. J Leukoc Biol 95(1):9–18. CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Long ME, Gong KQ, Volk JS, Eddy WE, Chang MY, Frevert CW, Altemeier WA, Gale M Jr, Liles WC, Manicone AM (2018) Matrix metalloproteinase 28 is regulated by TRIF- and type I IFN-dependent signaling in macrophages. Innate Immun 24(6):357–365. CrossRefPubMedGoogle Scholar
  79. 79.
    Werner SR, Dotzlaf JE, Smith RC (2008) MMP-28 as a regulator of myelination. BMC Neurosci 9:83. CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Smith DH (2009) Stretch growth of integrated axon tracts: extremes and exploitations. Prog Neurobiol 89(3):231–239. CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Kaneb HM, Folkmann AW, Belzil VV, Jao LE, Leblond CS, Girard SL, Daoud H, Noreau A, Rochefort D, Hince P, Szuto A, Levert A, Vidal S, Andre-Guimont C, Camu W, Bouchard JP, Dupre N, Rouleau GA, Wente SR, Dion PA (2015) Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis. Hum Mol Genet 24(5):1363–1373. CrossRefPubMedGoogle Scholar
  82. 82.
    Patil H, Cho KI, Lee J, Yang Y, Orry A, Ferreira PA (2013) Kinesin-1 and mitochondrial motility control by discrimination of structurally equivalent but distinct subdomains in Ran-GTP-binding domains of Ran-binding protein 2. Open Biol 3(3):120183. CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Cho KI, Yi H, Desai R, Hand AR, Haas AL, Ferreira PA (2009) RANBP2 is an allosteric activator of the conventional kinesin-1 motor protein, KIF5B, in a minimal cell-free system. EMBO Rep 10(5):480–486. CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Cho KI, Cai Y, Yi H, Yeh A, Aslanukov A, Ferreira PA (2007) Association of the kinesin-binding domain of RanBP2 to KIF5B and KIF5C determines mitochondria localization and function. Traffic 8:1722–1735CrossRefPubMedGoogle Scholar
  85. 85.
    Cai Y, Singh BB, Aslanukov A, Zhao H, Ferreira PA (2001) The docking of kinesins, KIF5B and KIF5C, to Ran-binding protein 2 (RanBP2) is mediated via a novel RanBP2 domain. J Biol Chem 276(45):41594–41602CrossRefPubMedGoogle Scholar
  86. 86.
    Yoshikawa F, Sato Y, Tohyama K, Akagi T, Furuse T, Sadakata T, Tanaka M, Shinoda Y, Hashikawa T, Itohara S, Sano Y, Ghandour MS, Wakana S, Furuichi T (2016) Mammalian-specific central myelin protein opalin is redundant for normal myelination: structural and behavioral assessments. PLoS One 11(11):e0166732. CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Parisi V, Manni G, Centofanti M, Gandolfi SA, Olzi D, Bucci MG (2001) Correlation between optical coherence tomography, pattern electroretinogram, and visual evoked potentials in open-angle glaucoma patients. Ophthalmology 108(5):905–912CrossRefPubMedGoogle Scholar
  88. 88.
    Parisi V (2001) Impaired visual function in glaucoma. Clin Neurophysiol 112(2):351–358CrossRefPubMedGoogle Scholar
  89. 89.
    Regan D, Milner BA, Heron JR (1976) Delayed visual perception and delayed visual evoked potentials in the spinal form of multiple sclerosis and in retrobulbar neuritis. Brain 99(1):43–66CrossRefPubMedGoogle Scholar
  90. 90.
    Holder GE (2004) Electrophysiological assessment of optic nerve disease. Eye (Lond) 18(11):1133–1143. CrossRefGoogle Scholar
  91. 91.
    Holder GE, Gale RP, Acheson JF, Robson AG (2009) Electrodiagnostic assessment in optic nerve disease. Curr Opin Neurol 22(1):3–10. CrossRefPubMedGoogle Scholar
  92. 92.
    Chiu IM, Morimoto ET, Goodarzi H, Liao JT, O’Keeffe S, Phatnani HP, Muratet M, Carroll MC, Levy S, Tavazoie S, Myers RM, Maniatis T (2013) A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep 4(2):385–401. CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Kapeli K, Pratt GA, Vu AQ, Hutt KR, Martinez FJ, Sundararaman B, Batra R, Freese P, Lambert NJ, Huelga SC, Chun SJ, Liang TY, Chang J, Donohue JP, Shiue L, Zhang J, Zhu H, Cambi F, Kasarskis E, Hoon S, Ares M Jr, Burge CB, Ravits J, Rigo F, Yeo GW (2016) Distinct and shared functions of ALS-associated proteins TDP-43, FUS and TAF15 revealed by multisystem analyses. Nat Commun 7:12143. CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Lagier-Tourenne C, Polymenidou M, Hutt KR, Vu AQ, Baughn M, Huelga SC, Clutario KM, Ling SC, Liang TY, Mazur C, Wancewicz E, Kim AS, Watt A, Freier S, Hicks GG, Donohue JP, Shiue L, Bennett CF, Ravits J, Cleveland DW, Yeo GW (2012) Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat Neurosci 15(11):1488–1497. CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Polymenidou M, Lagier-Tourenne C, Hutt KR, Huelga SC, Moran J, Liang TY, Ling SC, Sun E, Wancewicz E, Mazur C, Kordasiewicz H, Sedaghat Y, Donohue JP, Shiue L, Bennett CF, Yeo GW, Cleveland DW (2011) Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci 14(4):459–468. CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Martinez FJ, Pratt GA, Van Nostrand EL, Batra R, Huelga SC, Kapeli K, Freese P, Chun SJ, Ling K, Gelboin-Burkhart C, Fijany L, Wang HC, Nussbacher JK, Broski SM, Kim HJ, Lardelli R, Sundararaman B, Donohue JP, Javaherian A, Lykke-Andersen J, Finkbeiner S, Bennett CF, Ares M Jr, Burge CB, Taylor JP, Rigo F, Yeo GW (2016) Protein-RNA networks regulated by normal and ALS-associated mutant HNRNPA2B1 in the nervous system. Neuron 92(4):780–795. CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Rotem N, Magen I, Ionescu A, Gershoni-Emek N, Altman T, Costa CJ, Gradus T, Pasmanik-Chor M, Willis DE, Ben-Dov IZ, Hornstein E, Perlson E (2017) ALS along the axons—expression of coding and noncoding RNA differs in axons of ALS models. Sci Rep 7:44500. CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Brockington A, Ning K, Heath PR, Wood E, Kirby J, Fusi N, Lawrence N, Wharton SB, Ince PG, Shaw PJ (2013) Unravelling the enigma of selective vulnerability in neurodegeneration: motor neurons resistant to degeneration in ALS show distinct gene expression characteristics and decreased susceptibility to excitotoxicity. Acta Neuropathol 125(1):95–109. CrossRefPubMedGoogle Scholar
  99. 99.
    Stolt CC, Wegner M (2016) Schwann cells and their transcriptional network: evolution of key regulators of peripheral myelination. Brain Res 1641(Pt A):101–110. CrossRefPubMedGoogle Scholar
  100. 100.
    Yoshikawa F, Sato Y, Tohyama K, Akagi T, Hashikawa T, Nagakura-Takagi Y, Sekine Y, Morita N, Baba H, Suzuki Y, Sugano S, Sato A, Furuichi T (2008) Opalin, a transmembrane sialylglycoprotein located in the central nervous system myelin paranodal loop membrane. J Biol Chem 283(30):20830–20840. CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y, Lubischer JL, Krieg PA, Krupenko SA, Thompson WJ, Barres BA (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28(1):264–278. CrossRefPubMedGoogle Scholar
  102. 102.
    Milanesi E, Bonvicini C, Alberici A, Pilotto A, Cattane N, Premi E, Gazzina S, Archetti S, Gasparotti R, Cancelli V, Gennarelli M, Padovani A, Borroni B (2013) Molecular signature of disease onset in granulin mutation carriers: a gene expression analysis study. Neurobiol Aging 34(7):1837–1845. CrossRefPubMedGoogle Scholar
  103. 103.
    de Vet EC, Newland SA, Lyons PA, Aguado B, Campbell RD (2005) The cell surface receptor G6b, a member of the immunoglobulin superfamily, binds heparin. FEBS Lett 579(11):2355–2358. CrossRefPubMedGoogle Scholar
  104. 104.
    Currie E, Schulze A, Zechner R, Walther TC, Farese RV Jr (2013) Cellular fatty acid metabolism and cancer. Cell Metab 18(2):153–161. CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    White DT, Sengupta S, Saxena MT, Xu Q, Hanes J, Ding D, Ji H, Mumm JS (2017) Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina. Proc Natl Acad Sci USA 114(18):E3719–E3728. CrossRefPubMedGoogle Scholar
  106. 106.
    Zhang Y, Zhao L, Wang X, Ma W, Lazere A, Qian HH, Zhang J, Abu-Asab M, Fariss RN, Roger JE, Wong WT (2018) Repopulating retinal microglia restore endogenous organization and function under CX3CL1-CX3CR1 regulation. Sci Adv 4(3):eaap8492. CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Xu H, Chen M, Mayer EJ, Forrester JV, Dick AD (2007) Turnover of resident retinal microglia in the normal adult mouse. Glia 55(11):1189–1198. CrossRefPubMedGoogle Scholar
  108. 108.
    Muther PS, Semkova I, Schmidt K, Abari E, Kuebbeler M, Beyer M, Abken H, Meyer KL, Kociok N, Joussen AM (2010) Conditions of retinal glial and inflammatory cell activation after irradiation in a GFP-chimeric mouse model. Invest Ophthalmol Vis Sci 51(9):4831–4839. CrossRefPubMedGoogle Scholar
  109. 109.
    Kaplan A, Spiller KJ, Towne C, Kanning KC, Choe GT, Geber A, Akay T, Aebischer P, Henderson CE (2014) Neuronal matrix metalloproteinase-9 is a determinant of selective neurodegeneration. Neuron 81(2):333–348. CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Kiaei M, Kipiani K, Calingasan NY, Wille E, Chen J, Heissig B, Rafii S, Lorenzl S, Beal MF (2007) Matrix metalloproteinase-9 regulates TNF-alpha and FasL expression in neuronal, glial cells and its absence extends life in a transgenic mouse model of amyotrophic lateral sclerosis. Exp Neurol 205(1):74–81. CrossRefPubMedGoogle Scholar
  111. 111.
    Manicone AM, Gharib SA, Gong KQ, Eddy WE, Long ME, Frevert CW, Altemeier WA, Parks WC, Houghton AM (2017) Matrix metalloproteinase-28 is a key contributor to emphysema pathogenesis. Am J Pathol 187(6):1288–1300. CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Everts B, Amiel E, Huang SC, Smith AM, Chang CH, Lam WY, Redmann V, Freitas TC, Blagih J, van der Windt GJ, Artyomov MN, Jones RG, Pearce EL, Pearce EJ (2014) TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKvarepsilon supports the anabolic demands of dendritic cell activation. Nat Immunol 15(4):323–332. CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Wu Y, Prystowsky MB, Orlofsky A (1999) Sustained high-level production of murine chemokine C10 during chronic inflammation. Cytokine 11(7):523–530. CrossRefPubMedGoogle Scholar
  114. 114.
    Asensio VC, Lassmann S, Pagenstecher A, Steffensen SC, Henriksen SJ, Campbell IL (1999) C10 is a novel chemokine expressed in experimental inflammatory demyelinating disorders that promotes recruitment of macrophages to the central nervous system. Am J Pathol 154(4):1181–1191. CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Kanno M, Suzuki S, Fujiwara T, Yokoyama A, Sakamoto A, Takahashi H, Imai Y, Tanaka J (2005) Functional expression of CCL6 by rat microglia: a possible role of CCL6 in cell-cell communication. J Neuroimmunol 167(1–2):72–80. CrossRefPubMedGoogle Scholar
  116. 116.
    Nakajima H, Koizumi K (2014) Family with sequence similarity 107: a family of stress responsive small proteins with diverse functions in cancer and the nervous system (Review). Biomed Rep 2(3):321–325. CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Le PU, Angers-Loustau A, de Oliveira RM, Ajlan A, Brassard CL, Dudley A, Brent H, Siu V, Trinh G, Molenkamp G, Wang J, Seyed Sadr M, Bedell B, Del Maestro RF, Petrecca K (2010) DRR drives brain cancer invasion by regulating cytoskeletal-focal adhesion dynamics. Oncogene 29(33):4636–4647. CrossRefPubMedGoogle Scholar
  118. 118.
    Moreno-Mateos MA, Espina AG, Torres B, Gamez del Estal MM, Romero-Franco A, Rios RM, Pintor-Toro JA (2011) PTTG1/securin modulates microtubule nucleation and cell migration. Mol Biol Cell 22(22):4302–4311. CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Rizzo F, Riboldi G, Salani S, Nizzardo M, Simone C, Corti S, Hedlund E (2014) Cellular therapy to target neuroinflammation in amyotrophic lateral sclerosis. Cell Mol Life Sci 71(6):999–1015. CrossRefPubMedGoogle Scholar
  120. 120.
    O’Rourke JG, Bogdanik L, Yanez A, Lall D, Wolf AJ, Muhammad AK, Ho R, Carmona S, Vit JP, Zarrow J, Kim KJ, Bell S, Harms MB, Miller TM, Dangler CA, Underhill DM, Goodridge HS, Lutz CM, Baloh RH (2016) C9orf72 is required for proper macrophage and microglial function in mice. Science 351(6279):1324–1329. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of OphthalmologyDuke University Medical CenterDurhamUSA
  2. 2.Department of Ophthalmic ResearchCole Eye Institute, Cleveland Clinic FoundationClevelandUSA
  3. 3.Research ServiceLouis Stokes Cleveland Veterans Affairs Medical CenterClevelandUSA
  4. 4.Department of OphthalmologyCleveland Clinic Lerner College of Medicine of Case Western Reserve UniversityClevelandUSA

Personalised recommendations