The enemy within: Innate surveillance-mediated cell death, the common mechanism of neurodegenerative disease

Frontiers in Neuroscience

Volumn 10, Issue MAY, 2016, Pages

  Richards, Robert I ^a   Robertson, Sarah A ^b   O'Keefe, Louise V ^a   Fornarino, Dani ^a   Scott, Andrew ^a   Lardelli, Michael ^a   Baune, Bernhard T ^a  

^a UNIVERSITY OF ADELAIDE   (Australia)

^b UNIVERSITY OF ADELAIDE   (Australia)

Author keywords

Alzheimer's; Dementia; Huntington's; Inflammation; Innate autoimmunity; Neurodegeneration; Parkinson's

Indexed keywords

APOPTOTIC PROTEASE ACTIVATING FACTOR 1; MESSENGER RNA; PATTERN RECOGNITION RECEPTOR; TOLL LIKE RECEPTOR; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR ATFS; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; ARTICLE; AUTOPHAGY; BINDING AFFINITY; BRAIN ISCHEMIA; CANCER INCIDENCE; CELL DAMAGE; CELL DEATH; CELLS BY BODY ANATOMY; CYTOKINE RELEASE; CYTOKINE RESPONSE; DEGENERATIVE DISEASE; ENDOPLASMIC RETICULUM STRESS; ENVIRONMENTAL FACTOR; HUMAN; IMMUNE RESPONSE; IMMUNOSURVEILLANCE; INNATE IMMUNITY; MITOPHAGY; NECROPTOSIS; NONHUMAN; PARKINSON DISEASE; PATHOGENESIS; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN HOMEOSTASIS; PROTEIN SYNTHESIS; PROTEIN UNFOLDING; SOMATIC MUTATION;

EID: 84973532165     PISSN: 16624548     EISSN: 1662453X     Source Type: Journal    
DOI: 10.3389/fnins.2016.00193     Document Type: Article

References (202)

1. Ahmad, S. T., Sweeney, S. T., Lee, J. A., Sweeney, N. T., and Gao, F. B. (2009). Genetic screen identifies serpin5 as a regulator of the toll pathway and CHMP2B toxicity associated with frontotemporal dementia. Proc. Natl. Acad. Sci. U.S.A. 106, 12168-12173. doi: 10.1073/pnas.0903134106
2. Ahrens, S., Zelenay, S., Sancho, D., Hanc, P., Kjaer, S., Feest, C., et al. (2012). F-Actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells. Immunity 36, 635-645. doi: 10.1016/j.immuni.2012.03.008
3. Aikawa, T., Mogushi, K., Iijima-Tsutsui, K., Ishikawa, K., Sakurai, M., Tanaka, H., et al. (2015). Loss of MyD88 alters neuroinflammatory response and attenuates early Purkinje cell loss in a spinocerebellar ataxia type 6 mouse model. Hum. Molec. Genet. 24, 4780-4791. doi: 10.1093/hmg/ddv202
4. Andries, O., De Filette, M., De Smedt, S. C., Demeester, J., Van Poucke, M., Peelman, L., et al. (2013). Innate immune response and programmed cell death following carrier-mediated delivery of unmodified mRNA to respiratory cells. J. Contr. Rel. 167, 157-166. doi: 10.1016/j.jconrel.2013.01.033
5. Applequist, S. E., Wallin, R. P. A., and Ljunggren, H.-G. (2002). Variable expression of Toll-like receptors in murine innate and adaptive immune cell lines. Int. Immunol. 14, 1065-1074. doi: 10.1093/intimm/dxf069
6. Asakura, T., Ogura, K., and Goshima, Y. (2015). IRE-1/XBP-1 pathway of the unfolded protein response is required for properly localizing neuronal UNC-6/Netrin for axon guidance in C. elegans. Genes Cells 20, 153-159. doi: 10.1111/gtc.12206
7. Azuma, Y., Tokuda, T., Shimamura, M., Kyotani, A., Sasayama, H., Yoshida, T., et al. (2014). Identification of ter94, Drosophila VCP, as a strong modulator of motor neuron degeneration induced by knockdown of Caz, Drosophila FUS. Hum. Mol. Genet. 23, 3467-3480. doi: 10.1093/hmg/ddu055
8. Banez-Coronel, M., Porta, S., Kagerbauer, B., Mateu-Huertas, E., Pantano, L., Ferrer, I., et al. (2012). A pathogenic mechanism in Huntington's disease involves small CAG-repeated RNAs with neurotoxic activity. PLoS Genet 8:e1002481. doi: 10.1371/journal.pgen.1002481
9. Barbaro, B. A., Lukacsovich, T., Agrawal, N., Burke, J., Bornemann, D. J., Purcell, J. M., et al. (2015). Comparative study of naturally occurring huntingtin fragments in Drosophila points to exon 1 as the most pathogenic species in Huntington's disease. Hum. Mol. Genet. 24, 913-925. doi: 10.1093/hmg/ddu504
10. Batra, R., Charizanis, K., and Swanson, M. S. (2010). Partners in crime: bidirectional transcription in unstable microsatellite disease. Hum. Mol. Genet. 19, R77-R82. doi: 10.1093/hmg/ddq132
11. Batra, R., Hutt, K., Vu, A., Rabin, S. J., Baughn, M. W., Libby, R. T., et al. (2016). Gene expression signatures of sporadic ALS motor neuron populations. Biorvix. 4, 74. doi: 10.1101/038448
12. Bentmann, E., Haass, C., and Dormann, D. (2013). Stress granules in neurodegeneration-lessons learnt from TAR DNA binding protein of 43 kDa and fused in sarcoma. FEBS J. 280, 4348-4370. doi: 10.1111/febs.12287
13. Bernard, J. J., Cowing-Zitron, C., Nakatsuji, T., Muehleisen, B., Muto, J., Borkowski, A. W., et al. (2012). Ultraviolet radiation damages self noncoding RNA and is detected by TLR3. Nat. Med. 18, 1286-1290. doi: 10.1038/nm.2861
14. Bettens, K., Sleegers, K., and Van Broeckhoven, C. (2013). Genetic insights in Alzheimer's disease. Lancet Neurol. 12, 92-104. doi: 10.1016/S1474-4422(12)70259-4
15. Beutler, B., Eidenschenk, C., Crozat, K., Imler, J.-L., Takeuchi, O., Hoffman, J. A., et al. (2007). Genetic analysis of resistance to viral infection. Nat. Rev. Immunol. 7, 753-755. doi: 10.1038/nri2174
16. Bjorkqvist, M., Wild, E. J., Thiele, J., Silvestroni, A., Andre, R., Lahiri, N., et al. (2008). A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease. J. Exp. Med. 205, 1869-1877. doi: 10.1084/jem.20080178
17. Blin, J., and Fitzgerald, K. A. (2015). Perspective: the RNA exosome, cytokine gene regulation and links to autoimmunity. Cytokine 74, 175-180. doi: 10.1016/j.cyto.2015.03.005
18. Bortoluci, K. R., and Medzhitov, R. (2010). Control of infection by pyroptosis and autophagy: role of TLR and NLR. Cell. Molec. Life Sci. 67, 1643-1651. doi: 10.1007/s00018-010-0335-5
19. Brinkmann, M. M., Spooner, E., Hoebe, K., Beutler, B., Ploegh, H. L., and Kim, Y. M. (2007). The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling. J. Cell Biol. 177, 265-275. doi: 10.1083/jcb.200612056
20. Buchan, J. R., Kolaitis, R. M., Taylor, J. P., and Parker, R. (2013). Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell 153, 1461-1474. doi: 10.1016/j.cell.2013.05.037
21. Buchan, N., Silverman, N., and Cherry, S. (2014). Immunity in Drosophila melanogaster-from microbial recognition to whole-organism physiology. Nat. Rev. Immunol. 14, 796-810. doi: 10.1038/nri3763
22. Catalá-López, F., Suárez-Pinilla, M., Suárez-Pinilla, P., Valderas, J. M., Gómez-Beneyto, M., Martinez, S., et al. (2014). Inverse and direct cancer comorbidity in people with Central Nervous System disorders: a meta-analysis of Cancer incidence in 577, 013 participants of 50 observational studies. Psych. Psychosom. 83, 89-105. doi: 10.1159/000356498
23. Caulin, A. F., and Maley, C. C. (2011). Peto's paradox: evolution's prescription for Cancer prevention Trends Ecol. Evol. 26, 175-182. doi: 10.1016/j.tree.2011.01.002
24. Celardo, I., Martins, L. M., and Gandhi, S. (2014). Unravelling mitochondrial pathways in Parkinson's disease. Br. J. Pharmacol. 171, 1943-1957. doi: 10.1111/bph.12433
25. Chan, G., White, C. C., Winn, P. A., Cimpean, M., Replogle, J. M., Glick, L. R., et al. (2015). CD33 modulates TREM2: convergence of Alzheimer loci. Nat. Neurosci. 18, 1556-1558. doi: 10.1038/nn.4126
26. Chavan, S. S., Huerta, P. T., Robbiati, S., Valdes-Ferrer, S. I., Ochani, M., Dancho, M., et al. (2012). HMGB1 mediates cognitive impairment in sepsis survivors. Mol. Med. 18, 930-937. doi: 10.2119/molmed.2012.00195
27. Cho, J. A., Lee, A.-H., Platzer, B., Cross, B. C. S., Gardner, B. M., De Luca, H., et al. (2013). The unfolded protein response element IRE1a senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling. Cell Host Microbe 13, 558-569. doi: 10.1016/j.chom.2013.03.011
28. Christofferson, D. E., and Yuan, J. (2010). Necroptosis as an alternative form of programmed cell death. Curr. Opin. Cell Biol. 22, 263-268. doi: 10.1016/j.ceb.2009.12.003
29. Cornejo, V. H., and Hetz, C. (2013). The unfolded protein response in Alzheimer's disease. Semin. Immunopathol. 35, 277-292. doi: 10.1007/s00281-013-0373-9
30. Cox, L. E., Ferraiuolo, L., Goodall, E. F., Heath, P. R., Higginbottom, A., Mortiboys, H., et al. (2010). Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS). PLoS ONE 5:e9872. doi: 10.1371/journal.pone.0009872
31. Crow, Y. J. (2011). Type I interferonopathies: a novel set of inborn errors of immunity. Ann. N.Y. Acad. Sci. 1238, 91-98. doi: 10.1111/j.1749-6632.2011.06220.x
32. Crow, Y. J. (2015). Type I interferonopathies: mendelian type I interferon up-regulation. Curr. Opin. Immunol. 32, 7-12. doi: 10.1016/j.coi.2014.10.005
33. Crow, Y. J., and Rehwinkel, J. (2009). Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity. Hum. Mol. Genet. 18, R130-R136. doi: 10.1093/hmg/ddp293
34. Crow, Y. J., Zaki, M. S., Abdel-Hamid, M. S., Abdel-Salam, G., Boespflug-Tanguy, O., Cordeiro, N. J., et al. (2014). Mutations in ADAR1, IFIH1, and RNASEH2B presenting as Spastic Paraplegia. Neuropediatrics 6, 386-393. doi: 10.1055/s-0034-1389161
35. Dou, Z., Xu, C., Donahue, G., Shimi, T., Pan, J. A., Zhu, J., et al. (2015). Autophagy mediates degradation of nuclear lamina. Nature doi: 10.1038/nature15548
36. Driver, J. A., Beiser, A., Au, R., Kreger, B. E., Lee, G., Kurth, T., et al. (2012). Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study. BMJ 344:e1442. doi: 10.1136/bmj.e1442
37. Dunys, J., Duplan, E., and Checler, F. (2014). The transcription factor X-box binding protein-1 in neurodegenerative diseases. Mol. Neurodegener. 9:35. doi: 10.1186/1750-1326-9-35
38. Eckard, S. C., Rice, G. I., Fabre, A., Badens, C., Gray, E. E., Hartley, J. L., et al. (2014). The SKIV2L RNA exosome limits activation of the RIG-I-like receptors. Nat. Immunol. 15, 839-845. doi: 10.1038/ni.2948
39. Elmore, S. (2007). Apoptosis: a review of programmed cell death. Toxicol Pathol. 35, 495-516. doi: 10.1080/01926230701320337
40. Escott-Price, V., Bellenguez, C., Wang, L.-S., Choi, S.-H., Harold, D., Jones, L., et al. (2014). Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. PLoS ONE 9:e94661. doi: 10.1371/journal.pone.0094661
41. Fang, L., Hemion, C., Pinho Ferreira Bento, A. C., Bippes, C. C., et al. (2015). Mitochondrial function in neuronal cells depends on p97/VCP/Cdc48-mediated quality control. Front. Cell. Neurosci. 9:16. doi: 10.3389/fncel2015.00016
42. Feng, Y., and Martin, P. (2015). Imaging innate immune responses at tumour initiation: new insights from fish and flies. Nat. Rev. Cancer 15, 556-562. doi: 10.1038/nrc3979
43. Fonseca, A. C., Ferreiro, E., Oliveira, C. R., Cardoso, S. M., and Pereira, C. F. (2013). Activation of the endoplasmic reticulum stress response by the amyloid-beta 1-40 peptide in brain endothelial cells. Biochim. Biophys. Acta 1832, 2191-2203. doi: 10.1016/j.bbadis.2013.08.007
44. Francisco, N. M., Hsu, N.-J., Keeton, R., Randall, P., Sebesho, B., Allie, N., et al. (2015). TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis. J. Neuroinflam. 12, 125. doi: 10.1186/s12974-015-0345-1
45. Freibaum, B. D., Lu, Y., Lopez-Gonzalez, R., Kim, N. C., Almeida, S., Lee, K. H., et al. (2015). GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525, 129-133. doi: 10.1038/nature14974
46. Gardner, B. M., Pincus, D., Gotthardt, K., Gallagher, C. M., and Walter, P. (2013). Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harb. Perspect. Biol. 5:a013169. doi: 10.1101/cshperspect.a013169
47. Gelderblom, M., Sobey, C. G., Kleinschnitz, C., and Magnus, T. (2015). Danger signals in stroke. Ageing Res. Rev. 24(Pt A), 77-82. doi: 10.1016/j.arr.2015.07.004
48. Goedert, M. (2015). Alzheimer's and Parkinson's diseases: the prion concept in relation to assembled Ab, tau and α-synuclein. Science 349:1255555. doi: 10.1126/science.1255555
49. Goldwurm, S., Zini, M., Mariani, L., Tesel, S., Miceli, R., Sironi, F., et al. (2007). Evaluation of LRRK2 G2019S penetrance: relevance for genetic counseling in Parkinson disease. Neurobiology 68, 1141-1143. doi: 10.1212/01.wnl.0000254483.19854.ef
50. Gottschalk, W. K., Michael, W. L., He, Y. T., Saunders, A. M., Burns, D. K., Roses, A. D., et al. (2015). The broad impact of TOM40 on Neurodegenerative diseases in aging. J. Parkinsons Dis. Alzheimers Dis. 1, pii: 12. doi: 10.13188/2376-922X.1000003
51. Goubau, D., Rehwinkel, J., and Reis e Sousa, C. (2010). PYHIN proteins: center stage in DNA sensing. Nat. Immunol. 11, 984-986. doi: 10.1038/ni1110-984
52. Goubau, D., Schlee, M., Deddouche, S., Pruijssers, A. J., Zillinger, T., Goldeck, M., et al. (2014). Antiviral Immunity via RIG-I-mediated recognition of RNA bearing 5'-diphosphates. Nature 514, 372-375. doi: 10.1038/nature13590
53. Greene, J. C., Whitworth, A. J., Andrews, L. A., Parker, T. J., and Pallanck, L. J. (2005). Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis. Hum. Mol. Genet. 14, 799-811. doi: 10.1093/hmg/ddi074
54. Grundke-Iqbal, I., Iqbal, K., Quinlan, M., Tung, Y.-C., Zuidi, M. S., and Wisniewski, H. M. (1986). Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J. Biol. Chem. 261, 6084-6089.
55. Guardia-Laguarta, C. E., Area-Gomez, E., Rub, C., Liu, Y., Magrane, J., Becker, D., et al. (2014). α-synuclein is localized to mitochondria-associated ER membranes. J. Neurosci. 34, 249-259. doi: 10.1523/JNEUROSCI.2507-13.2014
56. Guillot-Sestler, M.-V., Doty, K. R., and Town, T. (2015). Innate immunity fights Alzheimer's disease. Trends Neurosci. 38, 674-681. doi: 10.1016/j.tins.2015.08.008
57. Haeusler, A. R., Donnelly, C. J., Periz, G., Simko, E. A., Shaw, P. G., Kim, M. S., et al. (2014). C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507, 195-200. doi: 10.1038/nature13124
58. Hamasaki, M., Furuta, N., Matsuda, A., Nezu, A., Yamamoto, A., Fujita, N., et al. (2013). Autophagosomes form at ER-mitochondria contact sites. Nature 495, 389-393. doi: 10.1038/nature11910
59. Hamilton, J. A. (1980). Macrophage stimulation and the inflammatory response to asbestos. Environ. Health Perspect. 34, 69-74. doi: 10.1289/ehp.803469
60. Harbauer, A. B., Zahedi, R. P., Sickmann, A., Pfanner, N., and Meisinger, C. (2014). The protein import Machinery of Mitochondria-a regulatory hub in metabolism, stress, and disease. Cell Metabol. 19, 357-372. doi: 10.1016/j.cmet.2014.01.010
61. Hardy, J. A., Bogdanovic, N., Winblad, B., Portelius, E., Andreasen, N., Cedazo-Minguez, A., et al. (2014). Pathways to Alzheimer's disease. J. Intern. Med. 275, 296-303. doi: 10.1111/joim.12192
62. Hardy, J. A., and Higgins, G. A. (1992). Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184-185. doi: 10.1126/science.1566067
63. Harijith, A., Ebenezer, D. L., and Natarajan, V. (2014). Reactive oxygen species at the crossroads of inflammasome and inflammation. Front. Physiol. 5:352. doi: 10.3389/fphys.2014.00352
64. Harris, H. E., Andersson, U., and Pisetsky, D. S. (2012). HMGB1: a multifunctional alarmin driving autoimmune and inflammatory disease. Nat. Rev. Rheumatol. 8, 195-202. doi: 10.1038/nrrheum.2011.222
65. Hausler, M., Schaade, L., Ramaekers, V. T., Doenges, M., Heimann, G., and Sellhaus, B. (2003). Inflammatory pseudotumours of the central nervous system: report of 3 cases and a literature review. Hum. Pathol. 34, 253-262. doi: 10.1053/hupa.2003.35
66. Haynes, C. M., and Ron, D. (2010). The mitochondrial UPR-protecting organelle protein homeostasis. J. Cell Sci. 123, 3849-3855. doi: 10.1242/jcs.075119
67. Haywood, A. F., and Staveley, B. E. (2004). Parkin counteracts symptoms in a Drosophila model of Parkinson's disease. BMC Neurosci. 5:14. doi: 10.1186/1471-2202-5-14
68. Hefendhel, J. K., Neher, J. J., Suhs, R. B., Kohsaka, S., Skodras, A., and amd Jucker, M. (2014). Homeostatic and injury-induced microglia behavior in the aging brain. Aging Cell 13, 60-69. doi: 10.1111/acel.12149
69. Heneka, M. T., Carson, M. J., El Khoury, J., Landreth, G. E., Brosseron, F., Feinstein, D. L., et al. (2015). Neuroinflammation in Alzheimer's disease. Lancet Neurol. 14, 388-405. doi: 10.1016/S1474-4422(15)70016-5
70. Heneka, M. T., Kummer, M. P., and Latz, E. (2014). Innate immune activation in neurodegenerative disease. Nat. Rev. Immunol. 14, 463-477. doi: 10.1038/nri3705
71. Heneka, M. T., and O'Banion, M. K. (2007). Inflammatory processes in Alzheimer's disease. J. Neuroimmunol. 184, 69-91. doi: 10.1016/j.jneuroim.2006.11.017
72. Herrup, K. (2015). The case for rejecting the amyloid cascade hypothesis. Nat. Neurosci. 18, 794-799. doi: 10.1038/nn.4017
73. Hetz, C., Thielen, P., Matus, S., Nassif, M., Court, F., Kiffin, R., et al. (2009). XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev. 23, 2294-2306. doi: 10.1101/gad.1830709
74. Higashiyama, H., Hirose, F., Yamaguchi, M., Inoue, Y. H., Fujikake, N., Matsukage, A., et al. (2002). Identification of ter94, Drosophila VCP, as a modulator of polyglutamine-induced neurodegeeration. Cell Death Differ. 9, 264-273. doi: 10.1038/sj.cdd.4400955
75. Hofer, M. J., and Campbell, I. L. (2013). Type I interferon in neurological disease-The devil from within. Cytokine Growth Factor Rev. 24, 257-267. doi: 10.1016/j.cytogfr.2013.03.006
76. Hornung, V., Hartmann, R., Ablasser, A., and Hopfner, K.-P. (2014). OAS proteins and cGAS: unifying concepts in sensing and responding to cytosolic nucleic acids. Nat. Rev. Immunol. 14, 521-528. doi: 10.1038/nri3719
77. Hu, S., Li, J., Xu, F., Mei, S., Le Duff, Y., Yin, L., et al. (2015). SAMHD1 Inhibits LINE-1 Retrotransposition by Promoting Stress Granule Formation. PLoS Genet. 11:e1005367. doi: 10.1371/journal.pgen.1005367
78. Iqbal, K., Alonso, A., del, C., Chen, S., Omar Chohan, M., El-Akkad, E., et al. (2005). Tau pathology in Alzhemier's disease and other tauopathies. Biochim. Biophys. Acta 1739, 198-210. doi: 10.1016/j.bbadis.2004.09.008
79. Iqbal, K., Grundke-Iqbal, I., Wisnieski, M., and Terry, R. D. (1977). On neurofilament and neurotubule proteins from human autopsy tissue. J. Neurochem. 29, 417-424. doi: 10.1111/j.1471-4159.1977.tb10689.x
80. Iqbal, K., Liu, F., and Gong, C.-X. (2015). Tau and neurodegenerative disease: the story so far. Nat. Rev. Neurol. 1, 15-27. doi: 10.1038/nrneurol.2015.225
81. Ito, D., and Suzuki, N. (2011). Conjoint pathologic cascades mediated by ALS/FTLD-U linked RNA-binding proteins TDP-43 and FUS. Neurology 77, 1636-1643. doi: 10.1212/WNL.0b013e3182343365
82. Iwashyna, T. J., Ely, E. W., Smith, D. M., and Langa, K. M. (2010). Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 304, 1787-1794. doi: 10.1001/jama.2010.1553
83. Juranek, J. K., Daffu, G. K., Wojtkiewicz, J., Lacomis, D., Kofler, J., and Schmidt, A. M. (2015). Receptor for Advanced Glycation end products and its inflammatory ligands are upregulated in Amyotrophic Lateral Sclerosis. Front. Cell Neurosci. 9:485. doi: 10.3389/fncel.2015.00485
84. Kaczmarek, A., Vandenabeele, P., and Krysko, D. V. (2013). Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 38, 209-223. doi: 10.1016/j.immuni.2013.02.003
85. Kaiser, W. J., Sridharan, H., Huang, C., Mandal, P., Upton, J. W., Gough, P. J., et al. (2013). Toll-like Receptor 3-mediated Necrosis via TRIF, RIP3, and MLKL. J. Biol. Chem. 288, 31268-31279. doi: 10.1074/jbc. M113.462341
86. Kanadia, R. N., Johnstone, K. A., Mankodi, A., Lungu, C., Thornton, C. A., Esson, D., et al. (2003). A muscleblind knockout model for myotonic dystrophy. Science 302, 1978-1980. doi: 10.1126/science.1088583
87. Kauppinen, T. M., Suh, S. W., Higashi, Y., Berman, A. E., Escartin, C., Won, S. J., et al. (2011). Poly(ADP-ribose) polymerase-1 modulates microglial responses to amyloid beta. J. Neuroinflammation 8:152. doi: 10.1186/1742-2094-8-152
88. Khoo, J. J., Forster, S., and Mansell, A. (2011). Toll-like receptors as interferon-regulated genes and their role in disease. J. Interferon. Cytokine Res. 31, 13-25. doi: 10.1089/jir.2010.0095
89. Kim, J. B., Sig Choi, J., Yu, Y. M., Nam, K., Piao, C. S., Kim, S. W., et al. (2006). HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in postischemic brain. J. Neurosci. 26, 6413-6421. doi: 10.1523/JNEUROSCI.3815-05.2006
90. Kim, Y. K., Shin, J., and Nahm, M. H. (2016). NOD-like receptors in infection, immunity, and disease. Yonsei. Med. J. 57, 5-14. doi: 10.3349/ymj.2016.57.1.5
91. Kiningham, K. K., Oberley, T. D., Lin, S.-M., Mattingly, C. A., and St. Clair, D. K. (1999). Overexpression of manganese superoxide dismutase protects against Mitochondrial-Initiated Poly(ADP-Ribose) polymerase-mediated cell death. FASEB J. 13, 1601-1610.
92. Kitada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura, Y., Minoshima, S., et al. (1998). Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605-608. doi: 10.1038/33416
93. Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Arozena, A. A., et al. (2016). Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12, 1-222.doi: 10.1080/15548627.2015.1100356
94. Kubes, P., and Mehal, W. Z. (2012). Sterile inflammation in the liver. Gastroenterology 143, 1158-1172. doi: 10.1053/j.gastro.2012.09.008
95. Laird, M. D., Shields, J. S., Sukumari-Ramesh, S., Kimbler, D. E., Fessler, R. D., Shakir, B., et al. (2014). High mobility group box protein-1 promotes cerebral edema after traumatic brain injury via activation of toll-like receptor 4. Glia. 62, 26-38. doi: 10.1002/glia.22581
96. Lattante, S., Ciura, S., Rouleau, G., and Kabashi, E. (2015). Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD). Trends Genet. 31, 263-273. doi: 10.1016/j.tig.2015.03.005
97. Lawlor, K. T., O'Keefe, L. V., Samaraweera, S. E., van Eyk, C. L., McLeod, C. J., Maloney, C. A., et al. (2011). Double-stranded RNA is pathogenic in Drosophila models of expanded repeat neurodegenerative diseases. Hum. Mol. Genet. 20, 3757-3768. doi: 10.1093/hmg/ddr292
98. Lee, J. H., Won, S. M., Suh, J., Son, S. J., Moon, G. J., Park, U.-J., et al. (2010). Induction of the unfolded protein response and cell death pathway in Alzheimer's disease, but not in aged Tg2576 mice. Exp. Mol. Med. 42, 386-394. doi: 10.3858/emm.2010.42.5.040
99. Lee, J. Y., Lee, J. Y., Lee, J. D., Phipps, S., Noakes, P. G., and Woodruff, T. M. (2015). Absence of toll-like receptor 4 (TLR4) extends survival in the hSOD1 G93A mouse model of amyotrophic lateral sclerosis. J. Neuroinflammation 12, 90. doi: 10.1186/s12974-015-0310-z
100. Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J.-M., and Hoffmann, J. A. (1996). The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in drosophila adults. Cell 86, 973-983. doi: 10.1016/S0092-8674(00)80172-5
101. Li, M.-J., Liu, C., Hu, X., Ma, C., Luo, X.-G., and Yan, X.-X. (2014). Inverse correlation between Alzheimer's disease and cancer: implication for a strong impact of regenerative propensity on neurodegeneration? BMC Neurol. 14:211. doi: 10.1186/s12883-014-0211-2
102. Li, Y. R., King, O. D., Shorter, J., and Gitler, A. D. (2013). Stress granules as crucibles of ALS pathogenesis. J. Cell Biol. 201, 361-372. doi: 10.1083/jcb.201302044
103. Liddicoat, B. J., Piskol, R., Chalk, A. M., Ramaswami, G., Higuchi, M., Hartner, J. C., et al. (2015). RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349, 1115-1120. doi: 10.1126/science.aac7049
104. Liu, Y., Samuel, B. S., Breen, P. C., and Ruvkun, G. (2014). Caenorhabditis elegans pathways that surveil and defend mitochondria. Nature 508, 406-410. doi: 10.1038/nature13204
105. Livingston, J. H., Lin, J. P., Dale, R. C., Gill, D., Brogan, P., Munnich, A., et al. (2014). A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1. J. Med. Genet. 51, 76-82. doi: 10.1136/jmedgenet-2013-102038
106. Loo, Y.-M., and Gale, M. (2011). Immune signalling by RIG-I-like receptors. Immunity 34, 680-692. doi: 10.1016/j.immuni.2011.05.003
107. Lu, J. V., Chen, H. C., and Walsh, C. M. (2014). Necroptotic signaling in adaptive and innate immunity. Sem. Cell. Develop. Biol. 35, 33-39. doi: 10.1016/j.semcdb.2014.07.003
108. Lui, P. C. W., Fan, Y. S., Wong, S. S., Chan, A. N. H., Wong, G., Chau, T. K. F., et al. (2009). Inflammatory pseudotumours of the central nervous system. Hum. Pathol. 40, 1611-1617. doi: 10.1016/j.humpath.2009.04.016
109. MacKay, C. R., Wang, J. P., and Kurt-Jones, E. A. (2014). Dicer's role as an antiviral: still an enigma. Curr. Opin. Immunol. 26, 49-55. doi: 10.1016/j.coi.2013.10.015
110. Mackenzie, I. R., Frick, P., Grässer, F. A., Gendron, T. F., Petrucelli, L., Cashman, N. R., et al. (2015). Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers. Acta Neuropathol. 6, 845-861. doi: 10.1007/s00401-015-1476-2
111. Mankodi, A., Logigian, E., Callahan, L., McClain, C., White, R., Henderson, D., et al. (2000). Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science 289, 1769-1772. doi: 10.1126/science.289.5485.1769
112. Mann, D. M. A. (2015). Dipeptide repeat protein toxicity in frontotemporal lobar degeneration and in motor neurone disease associated with expansions in C9ORF72da cautionary note. Neurobiol. Aging 36, 1224-1226. doi: 10.1016/j.neurobiolaging.2014.10.011
113. Martire, S., Mosca, L., and d'Erme, M. (2015). PARP-1 involvement in neurodegeneration: a focus on Alzheimer's and Parkinson's diseases. Mech. Ageing Devel. 146, 53-64. doi: 10.1016/j.mad.2015.04.001
114. Masters, C. L., Bateman, R., Blennow, K., Rowe, C. C., Sperling, R. A., and Cummings, J. L. (2015). Alzheimer's disease. Nat. Rev. Disease Primer. 1:15056. doi: 10.1038/nrdp.2015.56
115. McGlasson, S., Jury, A., Jackson, A., and Hunt, D. (2015). Type I interferon dysregulation and neurological disease. Nat. Rev. Neurol. 11, 515-523. doi: 10.1038/nrneurol.2015.143
116. McLeod, C. J., O'Keefe, L. V., and Richards, R. I. (2005). The pathogenic agent in Drosophila models of 'polyglutamine' diseases. Hum. Mol. Genet. 14, 1041-1048. doi: 10.1093/hmg/ddi096
117. Meyer, S. N., Amoyel, M., Bergantifios, C., de la Cova, C., Schertel, C., Basler, K., et al. (2014). An ancient defense system eliminates unfit cells from developing tissues during cell competition. Science 346:1258236. doi: 10.1126/science.1258236
118. Michels, M., Vieira, A. S., Vuolo, F., Zapelini, H. G., Mendonca, B., Mina, F., et al. (2015). The role of microglia activation in the development of sepsis-induced long-term cognitive impairment. Brain, Behav. Immun. 43, 54-59. doi: 10.1016/j.bbi.2014.07.002
119. Miller, J. R. C., Träger, U., Andre, R., Sarah, J., and Tabrizi, S. J. (2015). Mutant Huntingtin does not affect the Intrinsic Phenotype of Human Huntington's Disease T Lymphocytes. PLoS ONE 10:e0141793. doi: 10.1371/journal.pone.0141793
120. Mino, T., Murakawa, Y., Fukao, A., Vandenbon, A., Wessels, H.-H., Daisuke Ori, D., et al. (2015). Regnase-1 and roquin regulate a common element in inflammatory mRNAs by spatiotemporally distinct mechanisms. Cell 161, 1058-1073. doi: 10.1016/j.cell.2015.04.029
121. Mizuguchi, K., Parker, J. S., Blundell, T. L., and Gay, N. J. (1998). Getting knotted: a model for the structure and activation of Spätzle. Trends Biochem. Sci. 23, 239-242. doi: 10.1016/S0968-0004(98)01216-X
122. Moehle, M. S., Webber, P. J., Tse, T., Sukar, N., Standaert, D. G., DeSilva, T. M., et al. (2012). LRRK2 inhibition attenuates microglial inflammatory responses. J. Neurosci. 32, 1602-1611. doi: 10.1523/JNEUROSCI.5601-11.2012
123. Mosher, K. I., and Wyss-Coray, T. (2014). Microglial dysfunction in brain aging and Alzheimer's disease. Biochem. Pharmacol. 88, 594-604. doi: 10.1016/j.bcp.2014.01.008
124. Mudher, A., and Lovestone, S. (2002). Alzheimer's disease-do tauists and baptists finally shake hands? Trends Neurosci. 25, 22-26. doi: 10.1016/S0166-2236(00)02031-2
125. Muller-Schiffmann, A., Herring, A., Abdel-Hafiz, L., Chepkova, A. N., Schable, S., Wedel, D., et al. (2016). Amyloid-ß dimers in the absence of plaque pathology impair learning and synaptic plasticity. Brain 139(Pt 2), 509-525. doi: 10.1093/brain/awv355
126. Murakami, Y., Matsumoto, H., Roh, M., Giani, A., Kataoka, K., Morizane, Y., et al. (2014). Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration. Cell Death Differ. 21, 270-277. doi: 10.1038/cdd.2013.109
127. Musicco, M., Adorni, F., Di Santo, S., Prinelli, F., Pettenati, C., Caltagirone, C., et al. (2013). Inverse occurrence of cancer and Alzheimer disease: a population-based incidence study. Neurology 81, 322-328. doi: 10.1212/WNL.0b013e31829c5ec1
128. Nakano, S., Morimoto, S., Suzuki, S., Watanabe, T., Amano, H., and Takasaki, Y. (2010). Up-regulation of the endoplasmic reticulum transmembrane protein UNC93B in the B cells of patients with active systemic lupus erythematosus. Rheumatology 49, 876-881. doi: 10.1093/rheumatology/keq001
129. Nallagatla, S. R., Toroney, R., and Bevilacqua, P. C. (2008). A brilliant disguise for self RNA: 5'-end and internal modifications of primary transcripts suppress elements of innate immunity. RNA Biol. 5, 140-144. doi: 10.4161/rna.5.3.6839
130. Nasirudeen, A. M. A., Wong, H. H., Thien, P., Xu, S., Lam, K.-P., and Liu, D. X. (2011). RIG-I, MDA5 and TLR3 synergistically play and important role in restriction of Dengue Virus infection. PLoS NTDS 5:e926. doi: 10.1371/journal.pntd.0000926
131. Norris, K. L., Hao, R., Chen, L.-F., Lai, C.-H., Kapur, M., Shaughnessy, P. J., et al. (2015). Convergence of Parkin, PINK1, and α-synuclein on stress-induced mitochondrial morphological remodelling. J. Biol. Chem. 290, 13862-13874. doi: 10.1074/jbc. M114.634063
132. Nyström, S., Antoine, D. J., Lundbäck, P., Lock, J. G., Nita, A. F., Högstrand, K., et al. (2013). TLR activation regulates damage-associated molecular pattern isoforms released during pyroptosis. EMBO J. 32, 86-99. doi: 10.1038/emboj.2012.328
133. Olmos-Alonso, A., Schetters, S. T. T., Sri, S., Askew, K., Mancuso, R., Vargas-Caballero, M., et al. (2016). Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology. Brain 139(Pt 3), 891-907. doi: 10.1093/brain/awv379
134. Park, J., Lee, S. B., Lee, S., Kim, Y., Song, S., Kim, S., et al. (2006). Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441, 1157-1161. doi: 10.1038/nature04788
135. Pasparakis, M., and Vandenabeele, P. (2015). Necroptosis and its role in inflammation. Nature 517, 311-320. doi: 10.1038/nature14191
136. Pellegrino, M. W., and Haynes, C. M. (2015). Mitophagy and the mitochondrial unfolded protein response in neurodegeneration and bacterial infection. BMC Biol. 13:22. doi: 10.1186/s129-015-0129-1
137. Pellegrino, M. W., Nargund, A. M., Kirienko, N. V., Gillis, R., Fiorese, C. J., and Haynes, C. M. (2014). Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection. Nature 516, 414-418. doi: 10.1038/nature13818
138. Perry, V. H., and Holmes, C. (2014). Microglial priming in neurodegenerative disease. Nat. Rev. Neurol. 10, 217-224. doi: 10.1038/nrneurol.2014.38
139. Pestal, K., Funk, C. C., Snyder, J. M., Price, N. D., Treuring, P. M., and Stetson, D. B. (2015). Isoforms of RNA-Editing Enzyme ADAR1 independently control nucleic acid sensor MDA5-Driven autoimmunity and multi-organ development. Immunity 43, 933-944. doi: 10.1016/j.immuni.2015.11.001
140. Pestka, S., Krause, C. D., and Walter, M. R. (2004). Interferons, interferon-like cytokines, and their receptors. Immunol. Rev. 202, 8-32. doi: 10.1111/j.0105-2896.2004.00204.x
141. Piccoli, C., Ripoli, M., Quarato, G., Scrima, R., D'Aprile, A., Boffoli, D., et al. (2008). Coexistence of mutations in PINK1 and mitochondrial DNA in early onset parkinsonism. J. Med. Genet. 45, 596-602. doi: 10.1136/jmg.2008.058628
142. Poeck, H., Bschelder, M., Gross, O., Finger, K., Roth, S., Rebsamen, M., et al. (2010). Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production. Nat. Immunol. 11, 63-69. doi: 10.1038/ni.1824
143. Radian, A. D., de Almeide, L., Dorfleutner, A., and Stehlik, C. (2013). NLRP7 and related inflammasome activating pattern recognition receptors and their function in host defense and disease. Microb. Infect. 15, 630-639. doi: 10.1016/j.micinf.2013.04.001
144. Radian, A. D., Khare, S., Chu, L. H., Dorfleutner, A., and Stehlik, C. (2015). ATP binding by NLRP7 is required for inflammasome activation in response to bacterial lipopeptides. Mol. Immunol. 67, 294-302. doi: 10.1016/j.molimm.2015.06.013
145. Ray, R., Juranek, J. K., and Rai, V. (2015). RAGE axis in neuroinflammation, neurodegeneration and its emerging role in the pathogenesis of amyotrophic lateral sclerosis. Neurosci. Biobehav. Rev. 62, 48-55. doi: 10.1016/j.neubiorev.2015.12.006
146. Rhodes, J. D., Lott, M. C., Russell, S. L., Moulton, V., Sanderson, J., Wormstone, I. M., et al. (2012). Activation of the innate immune response and interferon signalling in myotonic dystrophy type 1 and type 2 cataracts. Hum. Mol. Genet. 21, 852-862. doi: 10.1093/hmg/ddr515
147. Rice, G. I., del Toro Duany, Y., Jenkinson, E. M., Forte, G. M., Anderson, B. H., Ariaudo, G., et al. (2014). Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat. Genet. 46, 503-509. doi: 10.1038/ng.2933
148. Rice, G. I., Kasher, P. R., Forte, G. M., Mannion, N. M., Greenwold, S. M., Szynklewicz, M., et al. (2012). Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature. Nat. Genet. 44, 1243-1248. doi: 10.1038/ng.2414
149. Rigby, R. E., and Rehwinkel, J. (2015). RNA degradation in antiviral immunity and autoimmunity. Trends Immunol. 36, 179-188. doi: 10.1016/j.it.2015.02.001
150. Roach, J. C., Glusman, G., Rowen, L., Kaur, A., Purcell, M. K., Smith, K. D., et al. (2005). The evolution of vertebrate Toll-like receptors. Proc. Natl. Acad. Sci. U.S.A. 102, 9577-9582. doi: 10.1073/pnas.0502272102
151. Rock, K. L., Latz, E., Ontiveros, F., and Kono, H. (2010). The sterile inflammatory response. Annu. Rev. Immunol. 28, 321-342. doi: 10.1146/annurev-immunol-030409-101311
152. Rodriguez-Vieitez, E., Saint-Aubert, L., Carter, S. F., Almkvist, O., Farid, K., Scholl, M., et al. (2016). Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease. Brain 139(Pt 3), 922-936. doi: 10.1093/brain/awv404
153. Roses, A. D., Lutz, M. W., Amrine-Madsen, H., Saunders, A. M., Crenshaw, D. G., Sundseth, S. S., et al. (2010). A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease. Pharmacogenomics J. 10, 375-384. doi: 10.1038/tpj.2009.69
154. Russo, I., Bubacco, L., and Greggio, E. (2014). LRRK2 and neuroinflammation: partners in crime in Parkinson's disease? J. Neuroinflammation 11:52. doi: 10.1186/1742-2094-11-52
155. Ryan, S. M., and Nolan, Y. M. (2016). Neuroinflammation negatively affects adult hippocampal neurogenesis and cognition: can exercise compensate? Neurosci. Biobehav. Rev. 61, 121-131. doi: 10.1016/j.neubiorev.2015.12.004
156. Ryoo, J., Choi, J., Oh, C., Kim, S., Seo, M., Kim, S.-Y., et al. (2014). The ribonuclease activity of SAMHD1 is required for HIV-1 restriction. Nat. Med. 20, 936-941. doi: 10.1038/nm.3626
157. Salminen, A., Kaarniranta, K., Kauppinen, A., Ojala, J., Haapasalo, A., Soininen, H., et al. (2013). Impaired autophagy and APP processing in Alzheimer's disease: the potential role of Beclin 1 interactome. Prog. Neurobiol. 106-107, 33-54. doi: 10.1016/j.pneurobio.2013.06.002
158. Samaraweera, S. E., O'Keefe, L. V., Price, G. R., Venter, D. J., and Richards, R. I. (2013). Distinct roles for Toll and autophagy pathways in double-stranded RNA toxicity in a Drosophila model of expanded repeat neurodegenerative diseases. Hum. Mol. Genet. 22, 2811-2819. doi: 10.1093/hmg/ddt130
159. Sasaki, T., Liu, K., Agari, T., Yasuhara, T., Mori-moto, J., Okazaki, M., et al. (2016). Anti-high mobility group box 1 antibody exerts neuroprotection in a rat model of Parkinson's disease. Exp. Neurol. 275(Pt 1), 220-231. doi: 10.1016/j.expneurol.2015.11.003
160. Saunders, A. M., Strittmatter, W. J., Schmechel, D., George-Hyslop, P. H., Pericak-Vance, M. A., Joo, S. H., et al. (1993). Association of apolipoprotein E allele e4 with late-onset familial and sporadic Alzheimers disease. Neurology 43, 1467-1472. doi: 10.1212/WNL.43.8.1467
161. Savage, C. D., Lopez-Castejon, G., Denes, A., and Brough, D. (2012). NLRP3-inflammasome activating DAMPs stimulate an inflammatory response in glia in the absence of priming which contributes to brain inflammation after injury. Front. Immunol. 3:288. doi: 10.3389/fimmu.2012.00288
162. Schapansky, J., Nardozzi, J. D., Felizia, F., and Lavoie, M. J. (2014). Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy. Hum. Mol. Genet. 23, 4201-4214. doi: 10.1093/hmg/ddu138
163. Schapansky, J., Nardozzi, J. D., and Lavoie, M. J. (2015). The complex relationship between microglia, alpha-synuclein, and LRRK2 in Parkinson's Disease. Neuroscience 302, 74-88. doi: 10.1016/j.neuroscience.2014.09.049
164. Schellenberg, G. D., and Montine, T. J. (2012). The genetics and neuropathology of Alzheimer's disease. Acta Neuropathol. 124, 305-323. doi: 10.1007/s00401-012-0996-2
165. Senft, D., and Ronai, Z. A. (2015). UPR, autophagy, and mitochondrial cross-talk underlies the ER stress response. Trends Biochem. Sci. 40, 141-148. doi: 10.1016/j.tibs.2015.01.002
166. Sharshar, T., Bozza, F., and Chretien, F. (2014). Neuropathological processes in sepsis. Lancet Neurol. 13, 534-536. doi: 10.1016/S1474-4422(14)70064-X
167. Shichita, T., Ito, M., and Yoshimura, A. (2014). Post-ischemic inflammation regulates neural damage and protection. Front. Cell. Neurosci. 8:319. doi: 10.3389/fncel.2014.00319
168. Simola, N., Morelli, M., and Carta, A. R. (2007). The 6-hydroxydopamine model of Parkinson's Disease. Neurotox. Res. 11, 151-167. doi: 10.1007/BF03033565
169. Sisodia, S. S. (1998). Nuclear inclusions in glutamine repeat disorders: are they pernicious, coincidental, or beneficial? Cell 95, 1-4. doi: 10.1016/S0092-8674(00)81743-2
170. Stein, D., and Nüsslein-Volhard, C. (1992). Multiple extracellular activities in Drosophila egg perivitelline fluid are required for establishment of embryonic dorsal-ventral polarity. Cell 68, 429-440. doi: 10.1016/0092-8674(92)90181-B
171. Talbot, K., and Ansorge, D. (2006). Recent advances in the genetics of amyotrophic lateral sclerosis and frontotemporal dementia: common pathways in neurodegenerative disease. Hum. Molec. Genet. 15, R182-R187. doi: 10.1093/hmg/ddl202
172. Tan, M.-S., Tan, L., Jiang, T., Zhu, X.-C., Wang, H.-F., and Jia, C.-D. (2014). Amyloid-ß induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer's disease. Cell Death Dis. 5:e1382. doi: 10.1038/cddis.2014.348
173. Tanner, C. M., Kamel, F., Ross, G. W., Hoppin, J. A., Goldman, S. M., Korell, M., et al. (2011). Rotenone, paraquat, and Parkinson's disease. Environ. Health Perspect. 119, 866-872. doi: 10.1289/ehp.1002839
174. Tanzi, R. E. (2012). The genetics of Alzheimer disease. Cold Spring Harb. Perspect. Med. 2:a006296. doi: 10.1101/cshperspect.a006296
175. Tekkok, I. H., Ventureyra, E. C., and Jimenez, C. L. (2000). Intracranial plasma cell granuloma. Brain Tumor. Path. 17, 97-103. doi: 10.1007/BF02484280
176. Thaiss, C. A., Levy, M., Itav, S., and Elinav, E. (2016). Integration of innate immune signaling. Trends Immunol. 37, 84-101. doi: 10.1016/j.it.2015.12.003
177. Thundyil, J., and Lim, K. L. (2015). DAMPs and neurodegeneration. Ageing Res. Rev. 24(Pt A), 17-28. doi: 10.1016/j.arr.2014.11.003
178. Valanne, S., Wang, J.-H., and Rämet, M. (2011). The Drosophila toll signaling pathway J. Immunol. 186, 649-656. doi: 10.4049/jimmunol.1002302
179. Valdes-Ferrer, S. I., Rosas-Ballina, M., Olofssan, P. S., Lu, B., Dancho, M. E., Ochani, M., et al. (2013). HMGB1 mediates splenomegaly and expansion of splenic CD11b+ Ly-yChigh inflammatory monocytes in murine sepsis survivors. J. Int. Med. 274, 381-390. doi: 10.1111/joim.12104
180. van Eyk, C. L., O'Keefe, L. V., Lawlor, K. T., Samaraweera, S. E., McLeod, C. J., Price, G. R., et al. (2011). Perturbation of the Akt/Gsk3-ß signalling pathway is common to Drosophila expressing expanded untranslated CAG, CUG and AUUCU repeat RNAs. Hum. Mol. Genet. 20, 2783-2794. doi: 10.1093/hmg/ddr177
181. Vanha-aho, L.-M., Valanne, S., and Rämet, M. (2015). Cytokines in Drosophila immunity. Immunol. Lett. 170, 42-51. doi: 10.1016/j.imlet.2015.12.005
182. Vendorova, K., Kabback, G., Abdel-Messih, E., Zhang, Y., Parks, R. J., Imai, Y., et al. (2009). Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease. Hum. Mol. Genet. 18, 4390-4404. doi: 10.1093/hmg/ddp394
183. Venereau, E., Ceriotti, C., and Bianchi, M. E. (2015). DAMPs from cell death to new life. Front. Immunol. 6:422. doi: 10.3389/fimmu.2015.00422
184. von Bernhardi, R., Tichauer, J. E., and Eugenin, J. (2010). Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders. J. Neurochemistry 112, 1099-1114. doi: 10.1111/j.1471-4159.2009.06537.x
185. Wan, J., Yourshaw, M., Mamsa, H., Rudnik-Schoneborn, S., Menezes, M. P., Hong, J. E., et al. (2012). Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration. Nat. Genet. 44, 704-708. doi: 10.1038/ng.2254
186. Warren, L., Manos, P. D., Ahfeldt, T., Loh, Y. H., Li, H., Lau, F., et al. (2007). Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7, 618-630. doi: 10.1016/j.stem.2010.08.012
187. Wen, H., Miao, E. A., and Ting, J. P. (2013). Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity 39, 432-441. doi: 10.1016/j.immuni.2013.08.037
188. West, R. J. H., Lu, Y., Marie, B., Gao, F.-B., and Sweeney, S. T. (2015). Rab8, POSH, and TAK1 regulate synaptic growth in a Drosophila model of frontotemporal dementia. J. Cell Biol. 208, 931-947. doi: 10.1083/jcb.201404066
189. Whitworth, A. J., Theodore, D. A., Greene, J. C., Benes, H., Wes, P. D., and Pallanck, L. J. (2005). Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease. Proc. Natl. Acad. Sci. U.S.A. 102, 8024-8029. doi: 10.1073/pnas.0501078102
190. Widmann, C. N., and Heneka, M. T. (2014). Long-term cerebral consequences of sepsis. Lancet Neurol. 13, 630-636. doi: 10.1016/S1474-4422(14)70017-1
191. Wu, W., Liu, P., and Li, J. (2012). Necroptosis: an emerging form of programmed cell death. Crit. Rev. Oncol. Hematol. 82, 249-258. doi: 10.1016/j.critrevonc.2011.08.004
192. Xu, Z., Poidevin, M., Li, X., Li, Y., Shu, L., Nelson, D. L., et al. (2013). Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc. Natl. Acad. Sci. U.S.A. 110, 7778-7783. doi: 10.1073/pnas.1219643110
193. Ye, X., Sun, X., Starovoytov, V., and Cai, Q. (2015). Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer's disease patient brains. Hum. Mol. Genet. 24, 2938-2951. doi: 10.1093/hmg/ddv056
194. Yoneyama, M., Jogi, M., and Onomoto, K. (2016). Regulation of antiviral innate immune signaling by stress-induced RNA granules. J. Biochem. 159, 279-286. doi: 10.1093/jb/mvv122
195. Yu, A. K., Song, L., Murray, K. D., van der List, D., Sun, C., Shen, Y., et al. (2015). Mitochondrial complex I deficiency leads to inflammation and retinal ganglion cell death in the Ndufs4 mouse. Hum. Mol. Genet. 24, 2848-2860. doi: 10.1093/hmg/ddv045
196. Yu, Z., Teng, X., and Bonini, N. M. (2011). Triplet repeat-derived siRNAs enhance RNA-mediated toxicity in a Drosophila model for myotonic dystrophy. PLoS Genet. 7:e1001340. doi: 10.1371/journal.pgen.1001340
197. Yuan, F., Dutta, T., Wang, L., Song, L., Gu, L., Qian, L., et al. (2015). Human DNA exonuclease TREX1 is also an exoribonuclease that acts on single-stranded RNA. J. Biol. Chem. 290, 13344-13353. doi: 10.1074/jbc. M115.653915
198. Zeng, L., Liu, Y.-P., Sha, H., Chen, H., Qi, L., and Smith, J. A. (2010). XBP-1 Couples ER Stress to Augmented IFN-ß Induction via a cis-acting enhancer in macrophages. J. Immunol. 185, 2324-2330. doi: 10.4049/jimmunol.0903052
199. Zetterberg, H., Smith, D. H., and Blennow, K. (2013). Biomarkers of mild traumatic brain injury in cerebrospinal fluid and blood. Nat. Rev. Neurol. 9, 201-210. doi: 10.1038/nrneurol.2013.9
200. Zhang, B., Gaiteri, C., Bodea, L.-G., Wang, Z., McElwee, J., Podtelezhnikov, A. A., et al. (2013). Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 153, 707-720. doi: 10.1016/j.cell.2013.03.030
201. Zhang, K., Donnelly, C. J., Haeusler, A. R., Grima, J. C., Machamer, J. B., Steinwald, P., et al. (2015). The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525, 56-61. doi: 10.1038/nature14973
202. Zhou, R., O'Hara, S. P., and Chen, X.-M. (2011). MicroRNA regulation of innate immune responses in epithelial cells. Cell. Mol. Immunol. 8, 371-379. doi: 10.1038/cmi.2011.19