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07.07.2018 | Original Article

FUS(1-359) transgenic mice as a model of ALS: pathophysiological and molecular aspects of the proteinopathy

verfasst von: Sergei Y. Funikov, Alexander P. Rezvykh, Pavel V. Mazin, Alexey V. Morozov, Andrey V. Maltsev, Maria M. Chicheva, Ekaterina A. Vikhareva, Mikhail B. Evgen’ev, Aleksey A. Ustyugov

Erschienen in: Neurogenetics | Ausgabe 3/2018

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Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that leads to the eventual death of motor neurons. Described cases of familial ALS have emphasized the significance of protein misfolding and aggregation of two functionally related proteins, FUS (fused in sarcoma) and TDP-43, implicated in RNA metabolism. Herein, we performed a comprehensive analysis of the in vivo model of FUS-mediated proteinopathy (ΔFUS(1-359) mice). First, we used the Noldus CatWalk system and confocal microscopy to determine the time of onset of the first clinical symptoms and the appearance of FUS-positive inclusions in the cytoplasm of neuronal cells. Second, we applied RNA-seq to evaluate changes in the gene expression profile encompassing the pre-symptomatic and the symptomatic stages of disease progression in motor neurons and the surrounding microglia of the spinal cord. The resulting data show that FUS-mediated proteinopathy is virtually asymptomatic in terms of both the clinical symptoms and the molecular aspects of neurodegeneration until it reaches the terminal stage of disease progression (120 days from birth). After this time, the pathological process develops very rapidly, resulting in the formation of massive FUS-positive inclusions accompanied by a transcriptional “burst” in the spinal cord cells. Specifically, it manifests in activation of a pro-inflammatory phenotype of microglial cells and malfunction of acetylcholine synapse transmission in motor neurons. Overall, we assume that the highly reproducible course of the pathological process, as well as the described accompanying features, makes ΔFUS(1-359) mice a convenient model for testing potential therapeutics against proteinopathy-induced decay of motor neurons.

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Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, Shaw PJ, Simmons Z, van den Berg LH (2017) Amyotrophic lateral sclerosis. Nat Rev Dis Primers 3:17071. https://doi.org/10.1038/nrdp.2017.71 PubMedCrossRef

Zarei S, Carr K, Reiley L, Diaz K, Guerra O, Altamirano PF, Pagani W, Lodin D, Orozco G, Chinea A (2015) A comprehensive review of amyotrophic lateral sclerosis. Surg Neurol Int 6:171. https://doi.org/10.4103/2152-7806.169561 PubMedPubMedCentralCrossRef

Hart PJ (2006) Pathogenic superoxide dismutase structure, folding, aggregation and turnover. Curr Opin Chem Biol 10(2):131–138. https://doi.org/10.1016/j.cbpa.2006.02.034 PubMedCrossRef

Neumann LM, El Ghouzzi V, Paupe V, Weber HP, Fastnacht E, Leenen A, Lyding S, Klusmann A, Mayatepek E, Pelz J, Cormier-Daire V (2006) Dyggve-Melchior-Clausen syndrome and Smith-McCort dysplasia: clinical and molecular findings in three families supporting genetic heterogeneity in Smith-McCort dysplasia. Am J Med Genet A 140(5):421–426. https://doi.org/10.1002/ajmg.a.31090 PubMedCrossRef

Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al-Chalabi A, Miller CC, Nicholson G, Shaw CE (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319(5870):1668–1672. https://doi.org/10.1126/science.1154584 PubMedCrossRef

Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323(5918):1208–1211. https://doi.org/10.1126/science.1165942 PubMedPubMedCentralCrossRef

Johnson JO, Mandrioli J, Benatar M, Abramzon Y, Van Deerlin VM, Trojanowski JQ, Gibbs JR, Brunetti M, Gronka S, Wuu J, Ding J, McCluskey L, Martinez-Lage M, Falcone D, Hernandez DG, Arepalli S, Chong S, Schymick JC, Rothstein J, Landi F, Wang YD, Calvo A, Mora G, Sabatelli M, Monsurro MR, Battistini S, Salvi F, Spataro R, Sola P, Borghero G, Consortium I, Galassi G, Scholz SW, Taylor JP, Restagno G, Chio A, Traynor BJ (2010) Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68(5):857–864. https://doi.org/10.1016/j.neuron.2010.11.036 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1038/nature08971 PubMedCrossRef

Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, Yang Y, Fecto F, Shi Y, Zhai H, Jiang H, Hirano M, Rampersaud E, Jansen GH, Donkervoort S, Bigio EH, Brooks BR, Ajroud K, Sufit RL, Haines JL, Mugnaini E, Pericak-Vance MA, Siddique T (2011) Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477(7363):211–215. https://doi.org/10.1038/nature10353 PubMedPubMedCentralCrossRef

10.

Shang Y, Huang EJ (2016) Mechanisms of FUS mutations in familial amyotrophic lateral sclerosis. Brain Res 1647:65–78. https://doi.org/10.1016/j.brainres.2016.03.036 PubMedPubMedCentralCrossRef

11.

Peters OM, Ghasemi M, Brown RH Jr (2015) Emerging mechanisms of molecular pathology in ALS. J Clin Invest 125(6):2548. https://doi.org/10.1172/JCI82693 PubMedPubMedCentralCrossRef

12.

Kraemer BC, Schuck T, Wheeler JM, Robinson LC, Trojanowski JQ, Lee VM, Schellenberg GD (2010) Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis. Acta Neuropathol 119(4):409–419. https://doi.org/10.1007/s00401-010-0659-0 PubMedPubMedCentralCrossRef

13.

Kuroda M, Sok J, Webb L, Baechtold H, Urano F, Yin Y, Chung P, de Rooij DG, Akhmedov A, Ashley T, Ron D (2000) Male sterility and enhanced radiation sensitivity in TLS(-/-) mice. EMBO J 19(3):453–462. https://doi.org/10.1093/emboj/19.3.453 PubMedPubMedCentralCrossRef

14.

Hicks GG, Singh N, Nashabi A, Mai S, Bozek G, Klewes L, Arapovic D, White EK, Koury MJ, Oltz EM, Van Kaer L, Ruley HE (2000) Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death. Nat Genet 24(2):175–179. https://doi.org/10.1038/72842 PubMedCrossRef

15.

Neumann M, Roeber S, Kretzschmar HA, Rademakers R, Baker M, Mackenzie IR (2009) Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol 118(5):605–616. https://doi.org/10.1007/s00401-009-0581-5 PubMedPubMedCentralCrossRef

16.

Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IR (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132(Pt 11):2922–2931. https://doi.org/10.1093/brain/awp214 PubMedPubMedCentralCrossRef

17.

Scekic-Zahirovic J, Sendscheid O, El Oussini H, Jambeau M, Sun Y, Mersmann S, Wagner M, Dieterle S, Sinniger J, Dirrig-Grosch S, Drenner K, Birling MC, Qiu J, Zhou Y, Li H, Fu XD, Rouaux C, Shelkovnikova T, Witting A, Ludolph AC, Kiefer F, Storkebaum E, Lagier-Tourenne C, Dupuis L (2016) Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss. EMBO J 35(10):1077–1097. https://doi.org/10.15252/embj.201592559 PubMedPubMedCentralCrossRef

18.

Orsini M, Oliveira AB, Nascimento OJ, Reis CH, Leite MA, de Souza JA, Pupe C, de Souza OG, Bastos VH, de Freitas MR, Teixeira S, Bruno C, Davidovich E, Smidt B (2015) Amyotrophic lateral sclerosis: new perpectives and update. Neurol Int 7(2):5885. https://doi.org/10.4081/ni.2015.5885 PubMedPubMedCentralCrossRef

19.

Farrawell NE, Lambert-Smith IA, Warraich ST, Blair IP, Saunders DN, Hatters DM, Yerbury JJ (2015) Distinct partitioning of ALS associated TDP-43, FUS and SOD1 mutants into cellular inclusions. Sci Rep 5:13416. https://doi.org/10.1038/srep13416 PubMedPubMedCentralCrossRef

20.

Weisberg SJ, Lyakhovetsky R, Werdiger AC, Gitler AD, Soen Y, Kaganovich D (2012) Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity. Proc Natl Acad Sci USA 109(39):15811–15816. https://doi.org/10.1073/pnas.1205829109 PubMedCrossRef

21.

Deng HX, Zhai H, Bigio EH, Yan J, Fecto F, Ajroud K, Mishra M, Ajroud-Driss S, Heller S, Sufit R, Siddique N, Mugnaini E, Siddique T (2010) FUS-immunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis. Ann Neurol 67(6):739–748. https://doi.org/10.1002/ana.22051 PubMedPubMedCentralCrossRef

22.

Yang W, Leystra-Lantz C, Strong MJ (2008) Upregulation of GSK3beta expression in frontal and temporal cortex in ALS with cognitive impairment (ALSci). Brain Res 1196:131–139. https://doi.org/10.1016/j.brainres.2007.12.031 PubMedCrossRef

23.

Kaganovich D, Kopito R, Frydman J (2008) Misfolded proteins partition between two distinct quality control compartments. Nature 454(7208):1088–1095. https://doi.org/10.1038/nature07195 PubMedPubMedCentralCrossRef

24.

Philips T, Rothstein JD (2015) Rodent models of amyotrophic lateral sclerosis. Curr Protoc Pharmacol 69:5.67.1–21. https://doi.org/10.1002/0471141755.ph0567s69 PubMedCrossRef

25.

Ahmed RM, Irish M, van Eersel J, Ittner A, Ke YD, Volkerling A, van der Hoven J, Tanaka K, Karl T, Kassiou M, Kril JJ, Piguet O, Gotz J, Kiernan MC, Halliday GM, Hodges JR, Ittner LM (2017) Mouse models of frontotemporal dementia: a comparison of phenotypes with clinical symptomatology. Neurosci Biobehav Rev 74(Pt A):126–138. https://doi.org/10.1016/j.neubiorev.2017.01.004 PubMedCrossRef

26.

McGoldrick P, Joyce PI, Fisher EM, Greensmith L (2013) Rodent models of amyotrophic lateral sclerosis. Biochim Biophys Acta 1832(9):1421–1436. https://doi.org/10.1016/j.bbadis.2013.03.012 PubMedCrossRef

27.

Van Damme P, Robberecht W, Van Den Bosch L (2017) Modelling amyotrophic lateral sclerosis: progress and possibilities. Dis Model Mech 10(5):537–549. https://doi.org/10.1242/dmm.029058 PubMedPubMedCentralCrossRef

28.

Murakami T, Yang SP, Xie L, Kawano T, Fu D, Mukai A, Bohm C, Chen F, Robertson J, Suzuki H, Tartaglia GG, Vendruscolo M, Kaminski Schierle GS, Chan FT, Moloney A, Crowther D, Kaminski CF, Zhen M, St George-Hyslop P (2012) ALS mutations in FUS cause neuronal dysfunction and death in Caenorhabditis elegans by a dominant gain-of-function mechanism. Hum Mol Genet 21(1):1–9. https://doi.org/10.1093/hmg/ddr417 PubMedCrossRef

29.

Xia R, Liu Y, Yang L, Gal J, Zhu H, Jia J (2012) Motor neuron apoptosis and neuromuscular junction perturbation are prominent features in a Drosophila model of Fus-mediated ALS. Mol Neurodegener 7:10. https://doi.org/10.1186/1750-1326-7-10 PubMedPubMedCentralCrossRef

30.

Huang C, Zhou H, Tong J, Chen H, Liu YJ, Wang D, Wei X, Xia XG (2011) FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PLoS Genet 7(3):e1002011. https://doi.org/10.1371/journal.pgen.1002011 PubMedPubMedCentralCrossRef

31.

Chen Y, Yang M, Deng J, Chen X, Ye Y, Zhu L, Liu J, Ye H, Shen Y, Li Y, Rao EJ, Fushimi K, Zhou X, Bigio EH, Mesulam M, Xu Q, Wu JY (2011) Expression of human FUS protein in Drosophila leads to progressive neurodegeneration. Protein Cell 2(6):477–486. https://doi.org/10.1007/s13238-011-1065-7 PubMedPubMedCentralCrossRef

32.

Devoy A, Kalmar B, Stewart M, Park H, Burke B, Noy SJ, Redhead Y, Humphrey J, Lo K, Jaeger J, Mejia Maza A, Sivakumar P, Bertolin C, Soraru G, Plagnol V, Greensmith L, Acevedo Arozena A, Isaacs AM, Davies B, Fratta P, Fisher EMC (2017) Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in ‘FUSDelta14’ knockin mice. Brain J Neurol 140(11):2797–2805. https://doi.org/10.1093/brain/awx248 CrossRef

33.

Shiihashi G, Ito D, Arai I, Kobayashi Y, Hayashi K, Otsuka S, Nakajima K, Yuzaki M, Itohara S, Suzuki N (2017) Dendritic homeostasis disruption in a novel frontotemporal dementia mouse model expressing cytoplasmic fused in sarcoma. EBioMedicine 24:102–115. https://doi.org/10.1016/j.ebiom.2017.09.005 PubMedPubMedCentralCrossRef

34.

Shelkovnikova TA, Peters OM, Deykin AV, Connor-Robson N, Robinson H, Ustyugov AA, Bachurin SO, Ermolkevich TG, Goldman IL, Sadchikova ER, Kovrazhkina EA, Skvortsova VI, Ling SC, Da Cruz S, Parone PA, Buchman VL, Ninkina NN (2013) Fused in sarcoma (FUS) protein lacking nuclear localization signal (NLS) and major RNA binding motifs triggers proteinopathy and severe motor phenotype in transgenic mice. J Biol Chem 288(35):25266–25274. https://doi.org/10.1074/jbc.M113.492017 PubMedPubMedCentralCrossRef

35.

Anders S, Pyl PT, Huber W (2015) HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics 31(2):166–169. https://doi.org/10.1093/bioinformatics/btu638 PubMedCrossRef

36.

Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29(1):15–21. https://doi.org/10.1093/bioinformatics/bts635 PubMedCrossRef

37.

Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30(15):2114–2120. https://doi.org/10.1093/bioinformatics/btu170 PubMedPubMedCentralCrossRef

38.

Krasnov GS, Dmitriev AA, Kudryavtseva AV, Shargunov AV, Karpov DS, Uroshlev LA, Melnikova NV, Blinov VM, Poverennaya EV, Archakov AI, Lisitsa AV, Ponomarenko EA (2015) PPLine: an automated pipeline for SNP, SAP, and splice variant detection in the context of proteogenomics. J Proteome Res 14(9):3729–3737. https://doi.org/10.1021/acs.jproteome.5b00490 PubMedCrossRef

39.

Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26(1):139–140. https://doi.org/10.1093/bioinformatics/btp616 PubMedCrossRef

40.

Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate—a practical and powerful approach to multiple testing, vol 57. https://doi.org/10.2307/2346101

41.

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. https://doi.org/10.1016/j.celrep.2013.06.018 PubMedPubMedCentralCrossRef

42.

Bandyopadhyay U, Cotney J, Nagy M, Oh S, Leng J, Mahajan M, Mane S, Fenton WA, Noonan JP, Horwich AL (2013) RNA-Seq profiling of spinal cord motor neurons from a presymptomatic SOD1 ALS mouse. PLoS One 8(1):e53575. https://doi.org/10.1371/journal.pone.0053575 PubMedPubMedCentralCrossRef

43.

Huang d W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4(1):44–57. https://doi.org/10.1038/nprot.2008.211 CrossRef

44.

Mazin P, Xiong J, Liu X, Yan Z, Zhang X, Li M, He L, Somel M, Yuan Y, Phoebe Chen YP, Li N, Hu Y, Fu N, Ning Z, Zeng R, Yang H, Chen W, Gelfand M, Khaitovich P (2013) Widespread splicing changes in human brain development and aging. Mol Syst Biol 9:633. https://doi.org/10.1038/msb.2012.67 PubMedPubMedCentralCrossRef

45.

Young MD, Wakefield MJ, Smyth GK, Oshlack A (2010) Gene ontology analysis for RNA-seq: accounting for selection bias. Genome Biol 11(2):R14. https://doi.org/10.1186/gb-2010-11-2-r14 PubMedPubMedCentralCrossRef

46.

Shelkovnikova TA, Robinson HK, Southcombe JA, Ninkina N, Buchman VL (2014) Multistep process of FUS aggregation in the cell cytoplasm involves RNA-dependent and RNA-independent mechanisms. Hum Mol Genet 23(19):5211–5226. https://doi.org/10.1093/hmg/ddu243 PubMedPubMedCentralCrossRef

47.

Shelkovnikova TA, Robinson HK, Connor-Robson N, Buchman VL (2013) Recruitment into stress granules prevents irreversible aggregation of FUS protein mislocalized to the cytoplasm. Cell Cycle 12(19):3194–3202. https://doi.org/10.4161/cc.26241 PubMedPubMedCentralCrossRef

48.

Okano T, Sasaki M, Fukada Y (2001) Cloning of mouse BMAL2 and its daily expression profile in the suprachiasmatic nucleus: a remarkable acceleration of Bmal2 sequence divergence after BMAL gene duplication. Neurosci Lett 300(2):111–114PubMedCrossRef

49.

Costa MJ, Finkenstadt B, Roche V, Levi F, Gould PD, Foreman J, Halliday K, Hall A, Rand DA (2013) Inference on periodicity of circadian time series. Biostatistics 14(4):792–806. https://doi.org/10.1093/biostatistics/kxt020 PubMedPubMedCentralCrossRef

50.

Ding H, Liu S, Yuan Y, Lin Q, Chan P, Cai Y (2011) Decreased expression of Bmal2 in patients with Parkinson’s disease. Neurosci Lett 499(3):186–188. https://doi.org/10.1016/j.neulet.2011.05.058 PubMedCrossRef

51.

Bosco P, Spada R, Caniglia S, Salluzzo MG, Salemi M (2014) Cerebellar degeneration-related autoantigen 1 (CDR1) gene expression in Alzheimer’s disease. Neurol Sci 35(10):1613–1614. https://doi.org/10.1007/s10072-014-1805-6 PubMedCrossRef

52.

Zhou ZD, Sathiyamoorthy S, Tan EK (2012) LINGO-1 and neurodegeneration: pathophysiologic clues for essential tremor. Tremor Other Hyperkinet Mov 2. https://doi.org/10.7916/D8PZ57JV

53.

Zhang Z, Xu X, Xiang Z, Yu Z, Feng J, He C (2013) LINGO-1 receptor promotes neuronal apoptosis by inhibiting WNK3 kinase activity. J Biol Chem 288(17):12152–12160. https://doi.org/10.1074/jbc.M112.447771 PubMedPubMedCentralCrossRef

54.

Sadri-Vakili G, Cha JH (2006) Histone deacetylase inhibitors: a novel therapeutic approach to Huntington’s disease (complex mechanism of neuronal death). Curr Alzheimer Res 3(4):403–408PubMedCrossRef

55.

Ryu JK, Kim SU, McLarnon JG (2003) Neuroprotective effects of pyruvate in the quinolinic acid rat model of Huntington’s disease. Exp Neurol 183(2):700–704PubMedCrossRef

56.

Lee J, Hong YK, Jeon GS, Hwang YJ, Kim KY, Seong KH, Jung MK, Picketts DJ, Kowall NW, Cho KS, Ryu H (2012) ATRX induction by mutant huntingtin via Cdx2 modulates heterochromatin condensation and pathology in Huntington’s disease. Cell Death Differ 19(7):1109–1116. https://doi.org/10.1038/cdd.2011.196 PubMedPubMedCentralCrossRef

57.

Phatnani HP, Guarnieri P, Friedman BA, Carrasco MA, Muratet M, O’Keeffe S, Nwakeze C, Pauli-Behn F, Newberry KM, Meadows SK, Tapia JC, Myers RM, Maniatis T (2013) Intricate interplay between astrocytes and motor neurons in ALS. Proc Natl Acad Sci U S A 110(8):E756–E765. https://doi.org/10.1073/pnas.1222361110 PubMedPubMedCentralCrossRef

58.

MacKeigan JP, Murphy LO, Blenis J (2005) Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance. Nat Cell Biol 7(6):591–600. https://doi.org/10.1038/ncb1258 PubMedCrossRef

59.

Qu Z, Zhang H, Huang M, Shi G, Liu Z, Xie P, Li H, Wang W, Xu G, Zhang Y, Yang L, Huang G, Takahashi JS, Zhang WJ, Xu Y (2016) Loss of ZBTB20 impairs circadian output and leads to unimodal behavioral rhythms. eLife 5. https://doi.org/10.7554/eLife.17171

60.

Nagao M, Ogata T, Sawada Y, Gotoh Y (2016) Zbtb20 promotes astrocytogenesis during neocortical development. Nat Commun 7:11102. https://doi.org/10.1038/ncomms11102 PubMedPubMedCentralCrossRef

61.

Lee S, Shang Y, Redmond SA, Urisman A, Tang AA, Li KH, Burlingame AL, Pak RA, Jovicic A, Gitler AD, Wang J, Gray NS, Seeley WW, Siddique T, Bigio EH, Lee VM, Trojanowski JQ, Chan JR, Huang EJ (2016) Activation of HIPK2 promotes ER stress-mediated neurodegeneration in amyotrophic lateral sclerosis. Neuron 91(1):41–55. https://doi.org/10.1016/j.neuron.2016.05.021 PubMedPubMedCentralCrossRef

62.

Geloso MC, Corvino V, Marchese E, Serrano A, Michetti F, D’Ambrosi N (2017) The dual role of microglia in ALS: mechanisms and therapeutic approaches. Front Aging Neurosci 9:242. https://doi.org/10.3389/fnagi.2017.00242 PubMedPubMedCentralCrossRef

63.

Thrash JC, Torbett BE, Carson MJ (2009) Developmental regulation of TREM2 and DAP12 expression in the murine CNS: implications for Nasu-Hakola disease. Neurochem Res 34(1):38–45. https://doi.org/10.1007/s11064-008-9657-1 PubMedCrossRef

64.

Melchior B, Garcia AE, Hsiung BK, Lo KM, Doose JM, Thrash JC, Stalder AK, Staufenbiel M, Neumann H, Carson MJ (2010) Dual induction of TREM2 and tolerance-related transcript, Tmem176b, in amyloid transgenic mice: implications for vaccine-based therapies for Alzheimer’s disease. ASN Neuro 2(3):e00037. https://doi.org/10.1042/AN20100010 PubMedPubMedCentralCrossRef

65.

Krook A (2008) IL-6 and metabolism-new evidence and new questions. Diabetologia 51(7):1097–1099. https://doi.org/10.1007/s00125-008-1019-7 PubMedCrossRef

66.

Palacz-Wrobel M, Borkowska P, Paul-Samojedny M, Kowalczyk M, Fila-Danilow A, Suchanek-Raif R, Kowalski J (2017) Effect of apigenin, kaempferol and resveratrol on the gene expression and protein secretion of tumor necrosis factor alpha (TNF-alpha) and interleukin-10 (IL-10) in RAW-264.7 macrophages. Biomed Pharmacother 93:1205–1212. https://doi.org/10.1016/j.biopha.2017.07.054 PubMedCrossRef

67.

Schmitt F, Hussain G, Dupuis L, Loeffler JP, Henriques A (2014) A plural role for lipids in motor neuron diseases: energy, signaling and structure. Front Cell Neurosci 8:25. https://doi.org/10.3389/fncel.2014.00025 PubMedPubMedCentralCrossRef

68.

Miana-Mena FJ, Gonzalez-Mingot C, Larrode P, Munoz MJ, Olivan S, Fuentes-Broto L, Martinez-Ballarin E, Reiter RJ, Osta R, Garcia JJ (2011) Monitoring systemic oxidative stress in an animal model of amyotrophic lateral sclerosis. J Neurol 258(5):762–769. https://doi.org/10.1007/s00415-010-5825-8 PubMedCrossRef

69.

Ilieva EV, Ayala V, Jove M, Dalfo E, Cacabelos D, Povedano M, Bellmunt MJ, Ferrer I, Pamplona R, Portero-Otin M (2007) Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis. Brain 130(Pt 12):3111–3123. https://doi.org/10.1093/brain/awm190 PubMedCrossRef

70.

Heras-Sandoval D, Perez-Rojas JM, Hernandez-Damian J, Pedraza-Chaverri J (2014) The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell Signal 26(12):2694–2701. https://doi.org/10.1016/j.cellsig.2014.08.019 PubMedCrossRef

71.

Qiu H, Lee S, Shang Y, Wang WY, Au KF, Kamiya S, Barmada SJ, Finkbeiner S, Lui H, Carlton CE, Tang AA, Oldham MC, Wang H, Shorter J, Filiano AJ, Roberson ED, Tourtellotte WG, Chen B, Tsai LH, Huang EJ (2014) ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects. J Clin Invest 124(3):981–999. https://doi.org/10.1172/JCI72723 PubMedPubMedCentralCrossRef

72.

Ederle H, Dormann D (2017) TDP-43 and FUS en route from the nucleus to the cytoplasm. FEBS Lett 591(11):1489–1507. https://doi.org/10.1002/1873-3468.12646 PubMedCrossRef

73.

Krug L, Chatterjee N, Borges-Monroy R, Hearn S, Liao WW, Morrill K, Prazak L, Rozhkov N, Theodorou D, Hammell M, Dubnau J (2017) Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS. PLoS Genet 13(3):e1006635. https://doi.org/10.1371/journal.pgen.1006635 PubMedPubMedCentralCrossRef

74.

Amlie-Wolf A, Ryvkin P, Tong R, Dragomir I, Suh E, Xu Y, Van Deerlin VM, Gregory BD, Kwong LK, Trojanowski JQ, Lee VM, Wang LS, Lee EB (2015) Transcriptomic changes due to cytoplasmic TDP-43 expression reveal dysregulation of histone transcripts and nuclear chromatin. PLoS One 10(10):e0141836. https://doi.org/10.1371/journal.pone.0141836 PubMedPubMedCentralCrossRef

75.

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. https://doi.org/10.1038/nn.2779 PubMedPubMedCentralCrossRef

76.

Irimia M, Weatheritt RJ, Ellis JD, Parikshak NN, Gonatopoulos-Pournatzis T, Babor M, Quesnel-Vallieres M, Tapial J, Raj B, O’Hanlon D, Barrios-Rodiles M, Sternberg MJ, Cordes SP, Roth FP, Wrana JL, Geschwind DH, Blencowe BJ (2014) A highly conserved program of neuronal microexons is misregulated in autistic brains. Cell 159(7):1511–1523. https://doi.org/10.1016/j.cell.2014.11.035 PubMedPubMedCentralCrossRef

77.

Marom A, Barak AF, Kramer MP, Lewinsky H, Binsky-Ehrenreich I, Cohen S, Tsitsou-Kampeli A, Kalchenko V, Kuznetsov Y, Mirkin V, Dezorella N, Shapiro M, Schwartzberg PL, Cohen Y, Shvidel L, Haran M, Becker-Herman S, Herishanu Y, Shachar I (2017) CD84 mediates CLL-microenvironment interactions. Oncogene 36(5):628–638. https://doi.org/10.1038/onc.2016.238 PubMedCrossRef

78.

Nasti TH, Cochran JB, Vachhani RV, McKay K, Tsuruta Y, Athar M, Timares L, Elmets CA (2017) IL-23 inhibits melanoma development by augmenting DNA repair and modulating T cell subpopulations. J Immunol 198(2):950–961. https://doi.org/10.4049/jimmunol.1601455 PubMedCrossRef

79.

Longtine MS, Cvitic S, Colvin BN, Chen B, Desoye G, Nelson DM (2017) Calcitriol regulates immune genes CD14 and CD180 to modulate LPS responses in human trophoblasts. Reproduction 154(6):735–744. https://doi.org/10.1530/REP-17-0183 PubMedCrossRef

80.

Fontaine M, Vogel I, Van Eycke YR, Galuppo A, Ajouaou Y, Decaestecker C, Kassiotis G, Moser M, Leo O (2018) Regulatory T cells constrain the TCR repertoire of antigen-stimulated conventional CD4 T cells. EMBO J 37(3):398–412. https://doi.org/10.15252/embj.201796881 PubMedCrossRef

81.

Kramer CD, Genco CA (2017) Microbiota, immune subversion, and chronic inflammation. Front Immunol 8:255. https://doi.org/10.3389/fimmu.2017.00255 PubMedPubMedCentralCrossRef

82.

Zuidscherwoude M, Worah K, van der Schaaf A, Buschow SI, van Spriel AB (2017) Differential expression of tetraspanin superfamily members in dendritic cell subsets. PLoS One 12(9):e0184317. https://doi.org/10.1371/journal.pone.0184317 PubMedPubMedCentralCrossRef

83.

Ambrose EC, Kornbluth J (2009) Downregulation of uridine-cytidine kinase like-1 decreases proliferation and enhances tumor susceptibility to lysis by apoptotic agents and natural killer cells. Apoptosis 14(10):1227–1236. https://doi.org/10.1007/s10495-009-0385-z PubMedCrossRef

84.

Dang AK, Tesfagiorgis Y, Jain RW, Craig HC, Kerfoot SM (2015) Meningeal infiltration of the spinal cord by non-classically activated B cells is associated with chronic disease course in a spontaneous B cell-dependent model of CNS autoimmune disease. Front Immunol 6:470. https://doi.org/10.3389/fimmu.2015.00470 PubMedPubMedCentralCrossRef

85.

Winkler EA, Sengillo JD, Sagare AP, Zhao Z, Ma Q, Zuniga E, Wang Y, Zhong Z, Sullivan JS, Griffin JH, Cleveland DW, Zlokovic BV (2014) Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice. Proc Natl Acad Sci U S A 111(11):E1035–E1042. https://doi.org/10.1073/pnas.1401595111 PubMedPubMedCentralCrossRef

86.

Jones TB (2014) Lymphocytes and autoimmunity after spinal cord injury. Exp Neurol 258:78–90. https://doi.org/10.1016/j.expneurol.2014.03.003 PubMedCrossRef

87.

Noristani HN, Sabourin JC, Gerber YN, Teigell M, Sommacal A, Vivanco M, Weber M, Perrin FE (2015) Brca1 is expressed in human microglia and is dysregulated in human and animal model of ALS. Mol Neurodegener 10(34):34. https://doi.org/10.1186/s13024-015-0023-x PubMedPubMedCentralCrossRef

88.

Grujic M, Bartholdy C, Remy M, Pinschewer DD, Christensen JP, Thomsen AR (2010) The role of CD80/CD86 in generation and maintenance of functional virus-specific CD8+ T cells in mice infected with lymphocytic choriomeningitis virus. J Immunol 185(3):1730–1743. https://doi.org/10.4049/jimmunol.0903894 PubMedCrossRef

89.

Nitschke L (2009) CD22 and Siglec-G: B-cell inhibitory receptors with distinct functions. Immunol Rev 230(1):128–143. https://doi.org/10.1111/j.1600-065X.2009.00801.x PubMedCrossRef

90.

Brandes M, Legler DF, Spoerri B, Schaerli P, Moser B (2000) Activation-dependent modulation of B lymphocyte migration to chemokines. Int Immunol 12(9):1285–1292PubMedCrossRef

91.

Seda V, Mraz M (2015) B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol 94(3):193–205. https://doi.org/10.1111/ejh.12427 PubMedCrossRef

92.

Koretzky GA, Abtahian F, Silverman MA (2006) SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond. Nat Rev Immunol 6(1):67–78. https://doi.org/10.1038/nri1750 PubMedCrossRef

93.

Sweeney P, Park H, Baumann M, Dunlop J, Frydman J, Kopito R, McCampbell A, Leblanc G, Venkateswaran A, Nurmi A, Hodgson R (2017) Protein misfolding in neurodegenerative diseases: implications and strategies. Transl Neurodegener 6:6. https://doi.org/10.1186/s40035-017-0077-5 PubMedPubMedCentralCrossRef

94.

Renton AE, Chio A, Traynor BJ (2014) State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 17(1):17–23. https://doi.org/10.1038/nn.3584 PubMedCrossRef

95.

Chen S, Sayana P, Zhang X, Le W (2013) Genetics of amyotrophic lateral sclerosis: an update. Mol Neurodegener 8:28. https://doi.org/10.1186/1750-1326-8-28 PubMedPubMedCentralCrossRef

96.

Julien JP, Kriz J (2006) Transgenic mouse models of amyotrophic lateral sclerosis. Biochim Biophys Acta 1762(11–12):1013–1024. https://doi.org/10.1016/j.bbadis.2006.03.006 PubMedCrossRef

97.

Lobsiger CS, Boillee S, Cleveland DW (2007) Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons. Proc Natl Acad Sci U S A 104(18):7319–7326. https://doi.org/10.1073/pnas.0702230104 PubMedPubMedCentralCrossRef

98.

Ferraiuolo L, Heath PR, Holden H, Kasher P, Kirby J, Shaw PJ (2007) Microarray analysis of the cellular pathways involved in the adaptation to and progression of motor neuron injury in the SOD1 G93A mouse model of familial ALS. J Neurosci 27(34):9201–9219. https://doi.org/10.1523/JNEUROSCI.1470-07.2007 PubMedCrossRef

99.

LaFlamme B (2015) Microexons on the brain. Nat Genet 47:105. https://doi.org/10.1038/ng.3207 CrossRef

100.

Porter RS, Jaamour F, Iwase S (2018) Neuron-specific alternative splicing of transcriptional machineries: implications for neurodevelopmental disorders. Mol Cell Neurosci 87:35–45. https://doi.org/10.1016/j.mcn.2017.10.006 PubMedCrossRef

101.

Luisier R, Tyzack GE, Hall CE, Mitchell JS, Devine H, Taha DM, Malik B, Meyer I, Greensmith L, Newcombe J, Ule J, Luscombe NM, Patani R (2018) Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS. Nat Commun 9(1):2010. https://doi.org/10.1038/s41467-018-04373-8 PubMedPubMedCentralCrossRef

102.

Sharma A, Lyashchenko AK, Lu L, Nasrabady SE, Elmaleh M, Mendelsohn M, Nemes A, Tapia JC, Mentis GZ, Shneider NA (2016) ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function. Nat Commun 7:10465. https://doi.org/10.1038/ncomms10465 PubMedPubMedCentralCrossRef

103.

Dodge JC, Treleaven CM, Fidler JA, Tamsett TJ, Bao C, Searles M, Taksir TV, Misra K, Sidman RL, Cheng SH, Shihabuddin LS (2013) Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis. Proc Natl Acad Sci U S A 110(26):10812–10817. https://doi.org/10.1073/pnas.1308421110 PubMedPubMedCentralCrossRef

104.

Shiihashi G, Ito D, Yagi T, Nihei Y, Ebine T, Suzuki N (2016) Mislocated FUS is sufficient for gain-of-toxic-function amyotrophic lateral sclerosis phenotypes in mice. Brain 139(Pt 9):2380–2394. https://doi.org/10.1093/brain/aww161 PubMedCrossRef

105.

E Hirbec H, Noristani HN, Perrin FE (2017) Microglia responses in acute and chronic neurological diseases: what microglia-specific transcriptomic studies taught (and did not teach) us. Front Aging Neurosci 9:227. https://doi.org/10.3389/fnagi.2017.00227 PubMedPubMedCentralCrossRef

106.

Liao B, Zhao W, Beers DR, Henkel JS, Appel SH (2012) Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS. Exp Neurol 237(1):147–152. https://doi.org/10.1016/j.expneurol.2012.06.011 PubMedPubMedCentralCrossRef

107.

Chio CC, Lin MT, Chang CP (2015) Microglial activation as a compelling target for treating acute traumatic brain injury. Curr Med Chem 22(6):759–770PubMedCrossRef

108.

Gravel M, Beland LC, Soucy G, Abdelhamid E, Rahimian R, Gravel C, Kriz J (2016) IL-10 controls early microglial phenotypes and disease onset in ALS caused by misfolded superoxide dismutase 1. J Neurosci 36(3):1031–1048. https://doi.org/10.1523/JNEUROSCI.0854-15.2016 PubMedCrossRef

109.

Macauley MS, Crocker PR, Paulson JC (2014) Siglec-mediated regulation of immune cell function in disease. Nat Rev Immunol 14(10):653–666. https://doi.org/10.1038/nri3737 PubMedPubMedCentralCrossRef

110.

Linnartz-Gerlach B, Kopatz J, Neumann H (2014) Siglec functions of microglia. Glycobiology 24(9):794–799. https://doi.org/10.1093/glycob/cwu044 PubMedCrossRef

111.

Mott RT, Ait-Ghezala G, Town T, Mori T, Vendrame M, Zeng J, Ehrhart J, Mullan M, Tan J (2004) Neuronal expression of CD22: novel mechanism for inhibiting microglial proinflammatory cytokine production. Glia 46(4):369–379. https://doi.org/10.1002/glia.20009 PubMedCrossRef

Titel: FUS(1-359) transgenic mice as a model of ALS: pathophysiological and molecular aspects of the proteinopathy
verfasst von: Sergei Y. Funikov
Alexander P. Rezvykh
Pavel V. Mazin
Alexey V. Morozov
Andrey V. Maltsev
Maria M. Chicheva
Ekaterina A. Vikhareva
Mikhail B. Evgen’ev
Aleksey A. Ustyugov
Publikationsdatum: 07.07.2018
Verlag: Springer Berlin Heidelberg
Erschienen in: Neurogenetics / Ausgabe 3/2018
Print ISSN: 1364-6745
Elektronische ISSN: 1364-6753
DOI: https://doi.org/10.1007/s10048-018-0553-9

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FUS(1-359) transgenic mice as a model of ALS: pathophysiological and molecular aspects of the proteinopathy

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