A perspective on stem cell modeling of amyotrophic lateral sclerosis

Cell Cycle

Volumn 14, Issue 23, 2015, Pages 3679-3688

  de Boer, A Sophie ^a,b   Eggan, Kevin ^a  

^a HOWARD HUGHES MEDICAL INSTITUTE   (United States)

^b LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

Amyotrophic lateral sclerosis; Astrocyte; Embryonic stem cells; Glia; Induced pluripotent stem cells; Microglia; Motor neuron

Indexed keywords

C9ORF72 PROTEIN; COPPER ZINC SUPEROXIDE DISMUTASE; FUSED IN SARCOMA PROTEIN; PROTEIN; TAR DNA BINDING PROTEIN; UNCLASSIFIED DRUG; VESICLE ASSOCIATED MEMBRANE PROTEIN-ASSOCIATED PROTEIN B; DNA BINDING PROTEIN; FUS PROTEIN, HUMAN; RNA BINDING PROTEIN FUS; SOD1 PROTEIN, HUMAN; SUPEROXIDE DISMUTASE; TDP-43 PROTEIN, HUMAN; VAPB PROTEIN, HUMAN; VESICULAR TRANSPORT PROTEIN;

AMYOTROPHIC LATERAL SCLEROSIS; ARTICLE; ASTROCYTE; EMBRYONIC STEM CELL; GENE MUTATION; HUMAN; IN VITRO STUDY; INDUCED PLURIPOTENT STEM CELL; MICROGLIA; MODEL; MOTONEURON; NONHUMAN; STEM CELL; CELL CULTURE TECHNIQUE; CELL DIFFERENTIATION; GENETICS; PATHOLOGY; PHYSIOLOGY;

AMYOTROPHIC LATERAL SCLEROSIS; ASTROCYTES; CELL CULTURE TECHNIQUES; CELL DIFFERENTIATION; DNA-BINDING PROTEINS; HUMANS; INDUCED PLURIPOTENT STEM CELLS; MICROGLIA; RNA-BINDING PROTEIN FUS; SUPEROXIDE DISMUTASE; SUPEROXIDE DISMUTASE-1; VESICULAR TRANSPORT PROTEINS;

EID: 84964026645     PISSN: 15384101     EISSN: 15514005     Source Type: Journal    
DOI: 10.1080/15384101.2015.1093712     Document Type: Article

References (81)

1. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993; 362: 59-62; PMID: 8446170; http://dx.doi.org/10.1038/362059a0
2. Gitcho MA, Baloh RH, Chakraverty S, Mayo K, Norton JB, Levitch D, Hatanpaa KJ, White CL, 3rd, Bigio EH, Caselli R, et al. TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 2008; 63: 535-8; PMID: 18288693; http://dx.doi.org/10.1002/ana.21344
3. Chow CY, Landers JE, Bergren SK, Sapp PC, Grant AE, Jones JM, Everett L, Lenk GM, McKenna-Yasek DM, Weisman LS, et al. Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. Am J Hum Genet 2009; 84: 85-8; PMID: 19118816; http://dx.doi.org/10.1016/j.ajhg.2008.12.010
4. Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 2009; 323: 1208-11; PMID: 19251628; http://dx.doi.org/10.1126/science.1165942
5. Kwiatkowski TJ, Jr., Bosco DA, Leclerc AL, Tamrazian E, VanderburgCR, RussC, Davis A,Gilchrist J, Kasarskis EJ, Munsat T, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 2009; 323: 1205-8; PMID: 19251627; http://dx.doi.org/10.1126/science.1166066
6. Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 2008; 319: 1668-72; PMID: 18309045; http://dx.doi.org/10.1126/science.1154584
7. Rutherford NJ, Zhang YJ, Baker M, Gass JM, Finch NA, Xu YF, Stewart H, Kelley BJ, Kuntz K, Crook RJ, et al. Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet 2008; 4: e1000193; PMID: 18802454; http://dx.doi.org/10.1371/journal.pgen.1000193
8. Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, Bouchard JP, Lacomblez L, Pochigaeva K, Salachas F, et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 2008; 40: 572-4; PMID: 18372902; http://dx.doi.org/10.1038/ng.132
9. Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011; 72: 257-68; PMID: 21944779; http://dx.doi.org/10.1016/j.neuron.2011.09.010
10. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011; 72: 245-56; PMID: 21944778; http://dx.doi.org/10.1016/j.neuron.2011.09.011
11. Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, Yang Y, Fecto F, Shi Y, Zhai H, et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 2011; 477: 211-5; PMID: 21857683; http://dx.doi.org/10.1038/nature10353
12. Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 2010; 465: 223-6; PMID: 20428114; http://dx.doi.org/10.1038/nature08971
13. Johnson JO,Mandrioli J, Benatar M, Abramzon Y, Van Deerlin VM, Trojanowski JQ, Gibbs JR, Brunetti M, Gronka S, Wuu J, et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 2010; 68: 857-64; PMID: 21145000; http://dx.doi.org/10.1016/j.neuron.2010.11.036
14. Yang C, Wang H, Qiao T, Yang B, Aliaga L, Qiu L, Tan W, Salameh J, McKenna-Yasek DM, Smith T, et al. Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 2014; 111: E1121-9; PMID: 24616503; http://dx.doi.org/10.1073/pnas.1322641111
15. Ripps ME, Huntley GW, Hof PR, Morrison JH, Gordon JW. Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 1995; 92: 689-93; PMID: 7846037; http://dx.doi.org/10.1073/pnas.92.3.689
16. Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX, et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 1994; 264: 1772-5; PMID: 8209258; http://dx.doi.org/10.1126/science.8209258
17. Gros-Louis F, Gaspar C, Rouleau GA. Genetics of familial and sporadic amyotrophic lateral sclerosis. Biochim Biophys Acta 2006; 1762: 956-72; PMID: 16503123; http://dx.doi.org/10.1016/j.bbadis.2006.01.004
18. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126: 663-76; PMID: 16904174; http://dx.doi.org/10.1016/j.cell.2006.07.024
19. Boulting GL, Kiskinis E, Croft GF, Amoroso MW, Oakley DH, Wainger BJ, Williams DJ, Kahler DJ, Yamaki M, Davidow L, et al. A functionally characterized test set of human induced pluripotent stem cells. Nat Biotechnol 2011; 29: 279-86; PMID: 21293464; http://dx.doi.org/10.1038/nbt.1783
20. Wichterle H, Lieberam I, Porter JA, Jessell TM. Directed differentiation of embryonic stem cells into motor neurons. Cell 2002; 110: 385-97; PMID: 12176325; http://dx.doi.org/10.1016/S0092-8674(02)00835-8
21. Amoroso MW, Croft GF, Williams DJ, O’Keeffe S, Carrasco MA, Davis AR, Roybon L, Oakley DH, Maniatis T, Henderson CE, et al. Accelerated highyield generation of limb-innervating motor neurons from human stem cells. J Neurosci 2013; 33: 574-86; PMID: 23303937; http://dx.doi.org/10.1523/JNEUROSCI.0906-12.2013
22. Aggarwal A, Nicholson G. Detection of preclinical motor neurone loss in SOD1 mutation carriers using motor unit number estimation. J Neurol Neurosurg Psychiatry 2002; 73: 199-201; PMID: 12122184; http://dx.doi.org/10.1136/jnnp.73.2.199
23. Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci 2007; 10: 608-14; PMID: 17435754; http://dx.doi.org/10.1038/nn1885
24. Yang YM, Gupta SK, Kim KJ, Powers BE, Cerqueira A, Wainger BJ, Ngo HD, Rosowski KA, Schein PA, Ackeifi CA, et al. A Small Molecule Screen in Stem-Cell-Derived Motor Neurons Identifies a Kinase Inhibitor as a Candidate Therapeutic for ALS. Cell Stem Cell 2013; 12: 713-26; PMID: 23602540; http://dx.doi.org/10.1016/j.stem.2013.04.003
25. Kiskinis E, Sandoe J,Williams LA, Boulting GL,Moccia R, Wainger BJ, Han S, Peng T, Thams S, Mikkilineni S, et al. Pathways Disrupted inHuman ALSMotorNeurons Identified through Genetic Correction of Mutant SOD1. Cell Stem Cell 2014; 14: 781-95; PMID: 24704492; http://dx.doi.org/10.1016/j.stem.2014.03.004
26. Wainger BJ, Kiskinis E, Mellin C, Wiskow O, Han SS, Sandoe J, Perez NP, Williams LA, Lee S, Boulting G, et al. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep 2014; 7: 1-11; PMID: 24703839; http://dx.doi.org/10.1016/j.celrep.2014.03.019
27. Fritz E, Izaurieta P,Weiss A,Mir FR, Rojas P, Gonzalez D, Rojas F, Brown RH, Jr.,Madrid R, vanZundert B. Mutant SOD1-expressing astrocytes release toxic factors that trigger motoneuron death by inducing hyperexcitability. J Neurophysiol 2013; 109: 2803-14; PMID: 23486205; http://dx.doi.org/10.1152/jn.00500.2012
28. Chen H, Qian K, Du Z, Cao J, Petersen A, Liu H, Blackbourn LWt, Huang CL, Errigo A, Yin Y, et al. Modeling ALS with iPSCs Reveals that Mutant SOD1 Misregulates Neurofilament Balance in Motor Neurons. Cell Stem Cell 2014; 14: 796-809; PMID: 24704493; http://dx.doi.org/10.1016/j.stem.2014.02.004
29. Tu PH, Raju P, Robinson KA, Gurney ME, Trojanowski JQ, Lee VM. Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions. Proc Natl Acad Sci U S A 1996; 93: 3155-60; PMID: 8610185; http://dx.doi.org/10.1073/pnas.93.7.3155
30. Egawa N, Kitaoka S, Tsukita K, Naitoh M, Takahashi K, Yamamoto T, Adachi F, Kondo T, Okita K, Asaka I, et al. Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci Transl Med; 4: 145ra04
31. Bilican B, Serio A, Barmada SJ, Nishimura AL, Sullivan GJ, Carrasco M, Phatnani HP, Puddifoot CA, Story D, Fletcher J, et al. Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proc Natl Acad Sci U S A 2012; 109: 5803-8; PMID: 22451909; http://dx.doi.org/10.1073/pnas.1202922109
32. Alami NH, Smith RB, Carrasco MA, Williams LA, Winborn CS, Han SS, Kiskinis E, Winborn B, Freibaum BD, Kanagaraj A, et al. Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron 2014; 81: 536-43; PMID: 24507191; http://dx.doi.org/10.1016/j.neuron.2013.12.018
33. Zhang Z, Almeida S, Lu Y, Nishimura AL, Peng L, Sun D, Wu B, Karydas AM, Tartaglia MC, Fong JC, et al. Downregulation of microRNA-9 in iPSC-derived neurons of FTD/ALS patients with TDP-43 mutations. PLoS One 2013; 8: e76055
34. Barmada SJ, Serio A, Arjun A, Bilican B, Daub A, Ando DM, Tsvetkov A, Pleiss M, Li X, Peisach D, et al. Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat Chem Biol 2014; 10: 677-85; PMID: 24974230; http://dx.doi.org/10.1038/nchembio.1563
35. Sareen D, O’Rourke JG, Meera P, Muhammad AK, Grant S, Simpkinson M, Bell S, Carmona S, Ornelas L, Sahabian A, et al. Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci Transl Med 2013; 5: 208ra149; PMID: 24154603
36. Donnelly CJ, Zhang PW, Pham JT, Heusler AR, Mistry NA, Vidensky S, Daley EL, Poth EM, Hoover B, Fines DM, et al. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 2013; 80: 415-28; PMID: 24139042; http://dx.doi.org/10.1016/j.neuron.2013.10.015
37. Levine TP, Daniels RD, Gatta AT,Wong LH,HayesMJ. The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics 2013; 29: 499-503; PMID: 23329412; http://dx.doi.org/10.1093/bioinformatics/bts725
38. Zhang D, Iyer LM, He F, Aravind L. Discovery of Novel DENN Proteins: Implications for the Evolution of Eukaryotic Intracellular Membrane Structures and Human Disease. Frontiers in genetics 2012; 3: 283; PMID: 23248642
39. Farg MA, Sundaramoorthy V, Sultana JM, Yang S, Atkinson RA, Levina V, Halloran MA, Gleeson PA, Blair IP, Soo KY, et al. C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet 2014; 23: 3579-95; PMID: 24549040; http://dx.doi.org/10.1093/hmg/ddu068
40. Haeusler AR, Donnelly CJ, Periz G, Simko EA, Shaw PG, Kim MS, Maragakis NJ, Troncoso JC, Pandey A, Sattler R, et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 2014; 507: 195-200; PMID: 24598541; http://dx.doi.org/10.1038/nature13124
41. Mori K, Lammich S, Mackenzie IR, Forne I, Zilow S, Kretzschmar H, Edbauer D, Janssens J, Kleinberger G, Cruts M, 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 2013; 125: 413-23; PMID: 23381195; http://dx.doi.org/10.1007/s00401-013-1088-7
42. Belzil VV, Bauer PO, Prudencio M, Gendron TF, Stetler CT, Yan IK, Pregent L, Daughrity L, Baker MC, Rademakers R, et al. Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood. Acta Neuropathol 2013; 126: 895-905; PMID: 24166615; http://dx.doi.org/10.1007/s00401-013-1199-1
43. Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, Kok F, Oliveira JR, Gillingwater T, Webb J, et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet 2004; 75: 822-31; PMID: 15372378; http://dx.doi.org/10.1086/425287
44. Skehel PA, Fabian-Fine R, Kandel ER. Mouse VAP33 is associated with the endoplasmic reticulum and microtubules. Proc Natl Acad Sci U S A 2000; 97: 1101-6; PMID: 10655491; http://dx.doi.org/10.1073/pnas.97.3.1101
45. Teuling E, Ahmed S, Haasdijk E, Demmers J, Steinmetz MO, Akhmanova A, Jaarsma D, Hoogenraad CC. Motor neuron disease-associated mutant vesicle-associated membrane protein-associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulumderived tubular aggregates. J Neurosci 2007; 27: 9801-15; PMID: 17804640; http://dx.doi.org/10.1523/JNEUROSCI.2661-07.2007
46. Wang L, Popko B, Roos RP. The unfolded protein response in familial amyotrophic lateral sclerosis. Hum Mol Genet 2011; 20: 1008-15; PMID: 21159797; http://dx.doi.org/10.1093/hmg/ddq546
47. Mitne-Neto M, Machado-Costa M, Marchetto MC, Bengtson MH, Joazeiro CA, Tsuda H, Bellen HJ, Silva HC, Oliveira AS, Lazar M, et al. Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients. Hum Mol Genet 2011; 20: 3642-52; PMID: 21685205; http://dx.doi.org/10.1093/hmg/ddr284
48. WatabeK, AkiyamaK, Kawakami E, Ishii T, EndoK, Yanagisawa H, SangoK, Tsukamoto M. Adenoviral expression of TDP-43 and FUS genes and shRNAs for protein degradation pathways in rodent motoneurons in vitro and in vivo. Neuropathology 2014; 34: 83-98; PMID: 23937386; http://dx.doi.org/10.1111/neup.12058
49. Burkhardt MF, Martinez FJ, Wright S, Ramos C, Volfson D,MasonM, Garnes J, Dang V, Lievers J, Shoukat-Mumtaz U, et al. A cellularmodel for sporadic ALS using patientderived induced pluripotent stem cells. Mol Cell Neurosci 2013; 56: 355-64; PMID: 23891805; http://dx.doi.org/10.1016/j.mcn.2013.07.007
50. Mekhoubad S, Bock C, de Boer AS, Kiskinis E, Meissner A, Eggan K. Erosion of dosage compensation impacts human iPSC disease modeling. Cell Stem Cell 2012; 10: 595-609; PMID: 22560080; http://dx.doi.org/10.1016/j.stem.2012.02.014
51. Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, Cleveland DW. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 2008; 11: 251-3; PMID: 18246065; http://dx.doi.org/10.1038/nn2047
52. Boillee S, Yamanaka K, LobsigerCS,CopelandNG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 2006; 312: 1389-92; PMID: 16741123; http://dx.doi.org/10.1126/science.1123511
53. Yamanaka K, Boillee S, Roberts EA, Garcia ML, McAlonis-Downes M, Mikse OR, Cleveland DW, Goldstein LS. Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice. Proc Natl Acad Sci U S A 2008; 105: 7594-9; PMID: 18492803; http://dx.doi.org/10.1073/pnas.0802556105
54. Wang L, Sharma K, Grisotti G, Roos RP. The effect of mutant SOD1 dismutase activity on non-cell autonomous degeneration in familial amyotrophic lateral sclerosis. Neurobiol Dis 2009; 35: 234-40; PMID: 19442735; http://dx.doi.org/10.1016/j.nbd.2009.05.002
55. Zhong Z, Deane R, Ali Z, Parisi M, Shapovalov Y, O’Banion MK, Stojanovic K, Sagare A, Boillee S, Cleveland DW, et al. ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat Neurosci 2008; 11: 420-2; PMID: 18344992; http://dx.doi.org/10.1038/nn2073
56. MillerTM, KimSH, Yamanaka K, HesterM, Umapathi P, Arnson H, Rizo L, Mendell JR, Gage FH, Cleveland DW, et al. Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 2006; 103: 19546-51; PMID: 17164329; http://dx.doi.org/10.1073/pnas.0609411103
57. Kang SH, Li Y, Fukaya M, Lorenzini I, Cleveland DW, Ostrow LW, Rothstein JD, Bergles DE. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci 2013; 16: 571-9; PMID: 23542689; http://dx.doi.org/10.1038/nn.3357
58. Marchetto MC, Muotri AR, Mu Y, Smith AM, Cezar GG, Gage FH. Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 2008; 3: 649-57; PMID: 19041781; http://dx.doi.org/10.1016/j.stem.2008.10.001
59. Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S. Astrocytes expressing ALSlinked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 2007; 10: 615-22; PMID: 17435755; http://dx.doi.org/10.1038/nn1876
60. Di Giorgio FP, Boulting GL, Bobrowicz S, Eggan KC. Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell 2008; 3: 637-48; PMID: 19041780; http://dx.doi.org/10.1016/j.stem.2008.09.017
61. Haidet-Phillips AM, Hester ME, Miranda CJ, Meyer K, Braun L, Frakes A, Song S, Likhite S, Murtha MJ, Foust KD, et al. Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 2011; 29: 824-8; PMID: 21832997; http://dx.doi.org/10.1038/nbt.1957
62. Re DB, Le Verche V, Yu C, Amoroso MW, Politi KA, Phani S, Ikiz B, Hoffmann L, Koolen M, Nagata T, et al. Necroptosis drives motor neuron death in models of both sporadic and familial ALS. Neuron 2014; 81: 1001-8; PMID: 24508385; http://dx.doi.org/10.1016/j.neuron.2014.01.011
63. de Boer AS, Koszka K, Kiskinis E, Suzuki N, Davis-Dusenbery BN, Eggan K. Genetic validation of a therapeutic target in a mouse model of ALS. Sci Transl Med 2014; 6: 248ra104; PMID: 25100738
64. Meyer K, Ferraiuolo L, Miranda CJ, Likhite S, McElroy S, Renusch S, Ditsworth D, Lagier-Tourenne C, Smith RA, Ravits J, et al. Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS. Proc Natl Acad Sci U S A 2014; 111: 829-32; PMID: 24379375; http://dx.doi.org/10.1073/pnas.1314085111
65. Serio A, Bilican B, Barmada SJ, Ando DM, Zhao C, Siller R, Burr K, Haghi G, Story D, Nishimura AL, et al. Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. Proc Natl Acad Sci U S A 2013; 110: 4697-702; PMID: 23401527; http://dx.doi.org/10.1073/pnas.1300398110
66. Heneka MT, Rodriguez JJ, Verkhratsky A. Neuroglia in neurodegeneration. Brain Res Rev 2010; 63: 189-211; PMID: 19944719; http://dx.doi.org/10.1016/j.brainresrev.2009.11.004
67. Almer G, Vukosavic S, Romero N, Przedborski S. Inducible nitric oxide synthase up-regulation in a transgenic mouse model of familial amyotrophic lateral sclerosis. JNeurochem 1999; 72: 2415-25; PMID: 10349851; http://dx.doi.org/10.1046/j.1471-4159.1999.0722415.x
68. Elliott JL. Cytokine upregulation in a murine model of familial amyotrophic lateral sclerosis. Brain Res Mol Brain Res 2001; 95: 172-8; PMID: 11687290; http://dx.doi.org/10.1016/S0169-328X(01)00242-X
69. Hensley K, Floyd RA, Gordon B, Mou S, Pye QN, Stewart C, West M, Williamson K. Temporal patterns of cytokine and apoptosis-related gene expression in spinal cords of the G93A-SOD1 mouse model of amyotrophic lateral sclerosis. J Neurochem 2002; 82: 365-74; PMID: 12124437; http://dx.doi.org/10.1046/j.1471-4159.2002.00968.x
70. Hensley K, Fedynyshyn J, Ferrell S, Floyd RA, Gordon B, Grammas P, Hamdheydari L, MhatreM, Mou S, Pye QN, et al. Message and protein-level elevation of tumor necrosis factor alpha (TNF alpha) and TNF alpha-modulating cytokines in spinal cords of the G93A-SOD1 mouse model for amyotrophic lateral sclerosis. Neurobiol Dis 2003; 14: 74-80; PMID: 13678668; http://dx.doi.org/10.1016/S0969-9961(03)00087-1
71. Yoshihara T, Ishigaki S, Yamamoto M, Liang Y, Niwa J, Takeuchi H, Doyu M, Sobue G. Differential expression of inflammation-and apoptosis-related genes in spinal cords of a mutant SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem 2002; 80: 158-67; PMID: 11796754; http://dx.doi.org/10.1046/j.0022-3042.2001.00683.x
72. Xiao Q, Zhao W, Beers DR, Yen AA, Xie W, Henkel JS, Appel SH. Mutant SOD1(G93A) microglia are more neurotoxic relative to wild-type microglia. J Neurochem 2007; 102: 2008-19; PMID: 17555556; http://dx.doi.org/10.1111/j.1471-4159.2007.04677.x
73. Beers DR, Henkel JS, Xiao Q, Zhao W, Wang J, Yen AA, Siklos L, McKercher SR, Appel SH. Wildtype microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 2006; 103: 16021-6; PMID: 17043238; http://dx.doi.org/10.1073/pnas.0607423103
74. ‘Hoing S, Rudhard Y, Reinhardt P, Glatza M, Stehling M, Wu G, Peiker C, Bocker A, Parga JA, Bunk E, et al. Discovery of inhibitors of microglial neurotoxicity acting through multiple mechanisms using a stem-cell-based phenotypic assay. Cell Stem Cell 2012; 11: 620-32; PMID: 23064101; http://dx.doi.org/10.1016/j.stem.2012.07.005
75. Frakes AE, Ferraiuolo L, Haidet-Phillips AM, Schmelzer L, Braun L, Miranda CJ, Ladner KJ, Bevan AK, Foust KD, Godbout JP, et al. Microglia induce motor neuron death via the classical NF-kappaB pathway in amyotrophic lateral sclerosis. Neuron 2014; 81: 1009-23; PMID: 24607225; http://dx.doi.org/10.1016/j.neuron.2014.01.013
76. Taketomi Y, Ueno N, Kojima T, Sato H, Murase R, Yamamoto K, Tanaka S, Sakanaka M, Nakamura M, Nishito Y, et al. Mast cellmaturation is driven via a group III phospholipase A2-prostaglandin D2-DP1 receptor paracrine axis. Nat Immunol 2013; 14: 554-63; PMID: 23624557; http://dx.doi.org/10.1038/ni.2586
77. Balestra B, Vicini R, Cremon C, Zecchi L, Dothel G, Vasina V, De Giorgio R, Paccapelo A, Pastoris O, Stanghellini V, et al. Colonic mucosal mediators from patients with irritable bowel syndrome excite enteric cholinergic motor neurons. Neurogastroenterol Motil 2012; 24: 1118-e570; PMID: 22937879; http://dx.doi.org/10.1111/nmo.12000
78. Zhang S, Grabauskas G, Wu X, Joo MK, Heldsinger A, Song I, Owyang C, Yu S. Role of prostaglandin D2 in mast cell activation-induced sensitization of esophageal vagal afferents. Am J Physiol Gastrointest Liver Physiol 2013; 304: G908-16; PMID: 23471341; http://dx.doi.org/10.1152/ajpgi.00448.2012
79. Ozdinler PH, Benn S, Yamamoto TH, Guzel M, Brown RH, Jr., Macklis JD. Corticospinal motor neurons and related subcerebral projection neurons undergo early and specific neurodegeneration in hSOD1G(9)(3)A transgenic ALS mice. J Neurosci 2011; 31: 4166-77; PMID: 21411657; http://dx.doi.org/10.1523/JNEUROSCI.4184-10.2011
80. Kiskinis E, Sandoe J, Williams LA, Boulting GL, Moccia R, Wainger BJ, Han S, Peng T, Thams S, Mikkilineni S, et al. Pathways Disrupted in Human ALS Motor Neurons Identified through Genetic Correction of Mutant SOD1. Cell Stem Cell 2014; 14(6): 781-95; PMID: 24704492; http://dx.doi.org/10.1016/j.stem.2014.03.004
81. Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med 1994; 330: 585-91; PMID: 8302340; http://dx.doi.org/10.1056/NEJM199403033300901