C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice

Scientific Reports

Volumn 6, Issue , 2016, Pages

  Atanasio, Amanda ^a   Decman, Vilma ^a   White, Derek ^a   Ramos, Meg ^a   Ikiz, Burcin ^a   Lee, Hoi Ching ^a   Siao, Chia Jen ^a   Brydges, Susannah ^a   Larosa, Elizabeth ^a   Bai, Yu ^a   Fury, Wen ^a   Burfeind, Patricia ^a   Zamfirova, Ralica ^a   Warshaw, Gregg ^a   Orengo, Jamie ^a   Oyejide, Adelekan ^a   Fralish, Michael ^a   Auerbach, Wojtek ^a   Poueymirou, William ^a   Freudenberg, Jan ^a   Gong, Guochun ^a   Zambrowicz, Brian ^a   Valenzuela, David ^a   Yancopoulos, George ^a   Murphy, Andrew ^a   Thurston, Gavin ^a   Lai, Ka Man Venus ^a   more..

^a REGENERON PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AUTOANTIBODY; C9ORF72 PROTEIN, MOUSE; CYTOKINE; GUANINE NUCLEOTIDE EXCHANGE FACTOR; TRANSCRIPTOME;

129 MOUSE; ANIMAL; AUTOIMMUNITY; BIOSYNTHESIS; BLOOD; C57BL MOUSE; FEMALE; GENETICS; IMMUNOLOGY; KNOCKOUT MOUSE; LYMPHOCYTE ACTIVATION; LYMPHOID TISSUE; MACROPHAGE; MALE; MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS; METABOLISM; PATHOLOGY; PLASMA CELL; SEQUENCE ANALYSIS; SYSTEMIC LUPUS ERYTHEMATOSUS;

ANIMALS; AUTOANTIBODIES; AUTOIMMUNITY; CYTOKINES; FEMALE; GLOMERULONEPHRITIS, MEMBRANOPROLIFERATIVE; GUANINE NUCLEOTIDE EXCHANGE FACTORS; LUPUS ERYTHEMATOSUS, SYSTEMIC; LYMPHOCYTE ACTIVATION; LYMPHOID TISSUE; MACROPHAGES; MALE; MICE, 129 STRAIN; MICE, INBRED C57BL; MICE, KNOCKOUT; PLASMA CELLS; SEQUENCE ANALYSIS, RNA; TRANSCRIPTOME;

EID: 84961128480     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/srep23204     Document Type: Article

References (65)

1. DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245-256 (2011).
2. Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257-268 (2011).
3. van Swieten, J. C. & Grossman, M. FTD/ALS families are no longer orphaned: the C9ORF72 story. Neurology 79, 962-964 (2012).
4. Donnelly, C. J., Grima, J. C. & Sattler, R. Aberrant RNA homeostasis in amyotrophic lateral sclerosis: potential for new therapeutic targets? Neurodegener. Dis. Manag. 4, 417-437 (2014).
5. Haeusler, A. R. et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507, 195-200 (2014).
6. Lee, Y. B. et al. Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep 5, 1178-1186 (2013).
7. Mori, K. et al. hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations. Acta Neuropathol 125, 413-423 (2013).
8. Porta, S., Kwong, L. K., Trojanowski, J. Q. & Lee, V. M. Drosha inclusions are new components of dipeptide-repeat protein aggregates in FTLD-TDP and ALS C9orf72 expansion cases. J Neuropathol Exp Neurol 74, 380-387 (2015).
9. Sareen, D. et al. Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci Transl Med 5, 208ra149 (2013).
10. Xu, Z. et al. Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc Natl Acad Sci USA 110, 7778-7783 (2013).
11. Ash, P. E. et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ ALS. Neuron 77, 639-646 (2013).
12. Mori, K. et al. Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. Acta Neuropathol 126, 881-893 (2013).
13. Mori, K. et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339, 1335-1338 (2013).
14. Zu, T. et al. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci USA 110, E4968-4977 (2013).
15. Stancu, I. C., Vasconcelos, B., Terwel, D. & Dewachter, I. Models of beta-amyloid induced Tau-pathology: the long and folded road to understand the mechanism. Mol Neurodegener 9, 51 (2014).
16. Gijselinck, I. et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol 11, 54-65 (2012).
17. Waite, A. J. et al. Reduced C9orf72 protein levels in frontal cortex of amyotrophic lateral sclerosis and frontotemporal degeneration brain with the C9ORF72 hexanucleotide repeat expansion. Neurobiol Aging 35, 1779 e1775-1779 e1713 (2014).
18. Fratta, P. et al. C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci Rep 2, 1016 (2012).
19. Reddy, K., Zamiri, B., Stanley, S. Y., Macgregor, R. B. Jr. & Pearson, C. E. The disease-associated r(GGGGCC)n repeat from the C9orf72 gene forms tract length-dependent uni-and multimolecular RNA G-quadruplex structures. J Biol Chem 288, 9860-9866 (2013).
20. Sket, P. et al. Characterization of DNA G-quadruplex species forming from C9ORF72 G4C2-expanded repeats associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Neurobiol Aging 36, 1091-1096 (2015).
21. Ciura, S. et al. Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis. Ann Neurol 74, 180-187 (2013).
22. Therrien, M., Rouleau, G. A., Dion, P. A. & Parker, J. A. Deletion of C9ORF72 results in motor neuron degeneration and stress sensitivity in C. elegans. PLoS One 8, e83450 (2013).
23. Koppers, M. et al. C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Ann Neurol 78, 426-438 (2015).
24. Lagier-Tourenne, C. et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci USA 110, E4530-4539 (2013).
25. Suzuki, N. et al. The mouse C9ORF72 ortholog is enriched in neurons known to degenerate in ALS and FTD. Nat Neurosci 16, 1725-1727 (2013).
26. Gill, A., Kidd, J., Vieira, F., Thompson, K. & Perrin, S. No benefit from chronic lithium dosing in a sibling-matched, gender balanced, investigator-blinded trial using a standard mouse model of familial ALS. PLoS One 4, e6489 (2009).
27. Heng, T. S., Painter, M. W. & Immunological Genome Project, C. The Immunological Genome Project: networks of gene expression in immune cells. Nat Immunol 9, 1091-1094 (2008).
28. Vignali, D. A. & Kuchroo, V. K. IL-12 family cytokines: immunological playmakers. Nat Immunol 13, 722-728 (2012).
29. Kilciksiz, S., Karakoyun-Celik, O., Agaoglu, F. Y. & Haydaroglu, A. A review for solitary plasmacytoma of bone and extramedullary plasmacytoma. Scientific World Journal 2012, 895765 (2012).
30. Palumbo, A. & Anderson, K. Multiple myeloma. N Engl J Med 364, 1046-1060 (2011).
31. Tarlinton, D. M. & Hodgkin, P. D. Targeting plasma cells in autoimmune diseases. J Exp Med 199, 1451-1454 (2004).
32. Browning, J. L. B cells move to centre stage: novel opportunities for autoimmune disease treatment. Nat Rev Drug Discov 5, 564-576 (2006).
33. Ingegnoli, F., Castelli, R. & Gualtierotti, R. Rheumatoid factors: clinical applications. Dis Markers 35, 727-734 (2013).
34. Kurts, C., Panzer, U., Anders, H. J. & Rees, A. J. The immune system and kidney disease: basic concepts and clinical implications. Nat Rev Immunol 13, 738-753 (2013).
35. Apostolidis, S. A., Lieberman, L. A., Kis-Toth, K., Crispin, J. C. & Tsokos, G. C. The dysregulation of cytokine networks in systemic lupus erythematosus. J Interferon Cytokine Res 31, 769-779 (2011).
36. Perry, D., Sang, A., Yin, Y., Zheng, Y. Y. & Morel, L. Murine models of systemic lupus erythematosus. J Biomed Biotechnol 2011, 271694 (2011).
37. Sherer, Y., Gorstein, A., Fritzler, M. J. & Shoenfeld, Y. Autoantibody explosion in systemic lupus erythematosus: more than 100 different antibodies found in SLE patients. Semin Arthritis Rheum 34, 501-537 (2004).
38. Xu, H. et al. Increased frequency of circulating follicular helper T cells in lupus patients is associated with autoantibody production in a CD40L-dependent manner. Cell Immunol 295, 46-51 (2015).
39. Migliorini, P., Baldini, C., Rocchi, V. & Bombardieri, S. Anti-Sm and anti-RNP antibodies. Autoimmunity 38, 47-54 (2005).
40. Kivity, S., Agmon-Levin, N., Zandman-Goddard, G., Chapman, J. & Shoenfeld, Y. Neuropsychiatric lupus: a mosaic of clinical presentations. BMC Med 13, 43 (2015).
41. Gulinello, M. & Putterman, C. The MRL/lpr mouse strain as a model for neuropsychiatric systemic lupus erythematosus. J Biomed Biotechnol 2011, 207504 (2011).
42. Zandman-Goddard, G., Chapman, J. & Shoenfeld, Y. Autoantibodies involved in neuropsychiatric SLE and antiphospholipid syndrome. Semin Arthritis Rheum 36, 297-315 (2007).
43. Sciascia, S., Bertolaccini, M. L., Roccatello, D., Khamashta, M. A. & Sanna, G. Autoantibodies involved in neuropsychiatric manifestations associated with systemic lupus erythematosus: a systematic review. J Neurol 261, 1706-1714 (2014).
44. Zivkovic, S. Autoimmune neurologic disorders. Curr Neuropharmacol 9, 399 (2011).
45. Nataf, S. & Pays, L. Gene co-expression analysis unravels a link between C9orf72 and RNA metabolism in myeloid cells. Acta Neuropathol Commun 3, 64 (2015).
46. Muller, M., Emmendorffer, A. & Lohmann-Matthes, M. L. Expansion and high proliferative potential of the macrophage system throughout life time of lupus-prone NZB/W and MRL lpr/lpr mice. Lack of down-regulation of extramedullar macrophage proliferation in the postnatal period. Eur J Immunol 21, 2211-2217 (1991).
47. Herrmann, M. et al. Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum 41, 1241-1250 (1998).
48. Potter, P. K., Cortes-Hernandez, J., Quartier, P., Botto, M. & Walport, M. J. Lupus-prone mice have an abnormal response to thioglycolate and an impaired clearance of apoptotic cells. J Immunol 170, 3223-3232 (2003).
49. Shao, W. H. & Cohen, P. L. Disturbances of apoptotic cell clearance in systemic lupus erythematosus. Arthritis Res Ther 13, 202 (2011).
50. Zhou, X. J. et al. Genetic association of PRDM1-ATG5 intergenic region and autophagy with systemic lupus erythematosus in a Chinese population. Ann Rheum Dis 70, 1330-1337 (2011).
51. Zhang, Y. M. et al. Rare Variants of ATG5 Are Likely to Be Associated With Chinese Patients With Systemic Lupus Erythematosus. Medicine (Baltimore) 94, e939 (2015).
52. Fernandez, D. R. et al. Activation of mammalian target of rapamycin controls the loss of TCRzeta in lupus T cells through HRES-1/ Rab4-regulated lysosomal degradation. J Immunol 182, 2063-2073 (2009).
53. Clarke, A. J. et al. Autophagy is activated in systemic lupus erythematosus and required for plasmablast development. Ann Rheum Dis 74, 912-920 (2015).
54. Pierdominici, M. et al. Role of autophagy in immunity and autoimmunity, with a special focus on systemic lupus erythematosus. FASEB J 26, 1400-1412 (2012).
55. Towns, R. et al. Sera from patients with type 2 diabetes and neuropathy induce autophagy and colocalization with mitochondria in SY5Y cells. Autophagy 1, 163-170 (2005).
56. Farg, M. A. et al. C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet 23, 3579-3595 (2014).
57. Xiao, S. et al. Isoform-specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis. Ann Neurol 78, 568-583 (2015).
58. Freibaum, B. D. et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525, 129-133 (2015).
59. Jovicic, A. et al. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci 18, 1226-1229 (2015).
60. Zhang, K. et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525, 56-61 (2015).
61. Dechiara, T. M. et al. VelociMouse: fully ES cell-derived F0-generation mice obtained from the injection of ES cells into eight-cellstage embryos. Methods Mol Biol 530, 311-324 (2009).
62. DeChiara, T. M. et al. Producing fully ES cell-derived mice from eight-cell stage embryo injections. Methods Enzymol 476, 285-294 (2010).
63. Poueymirou, W. T. et al. F0 generation mice fully derived from gene-targeted embryonic stem cells allowing immediate phenotypic analyses. Nat Biotechnol 25, 91-99 (2007).
64. Valenzuela, D. M. et al. High-throughput engineering of the mouse genome coupled with high-resolution expression analysis. Nat Biotechnol 21, 652-659 (2003).
65. Frazier, K. S. et al. Proliferative and nonproliferative lesions of the rat and mouse urinary system. Toxicol Pathol 40, 14S-86S (2012).