Suscripción a Biblioteca: Guest
Portal Digitalde Biblioteca Digital eLibros Revistas Referencias y Libros de Ponencias Colecciones
Critical Reviews™ in Eukaryotic Gene Expression
Factor de Impacto: 2.156 Factor de Impacto de 5 años: 2.255 SJR: 0.649 SNIP: 0.599 CiteScore™: 3

ISSN Imprimir: 1045-4403
ISSN En Línea: 2162-6502

Volumen 30, 2020 Volumen 29, 2019 Volumen 28, 2018 Volumen 27, 2017 Volumen 26, 2016 Volumen 25, 2015 Volumen 24, 2014 Volumen 23, 2013 Volumen 22, 2012 Volumen 21, 2011 Volumen 20, 2010 Volumen 19, 2009 Volumen 18, 2008 Volumen 17, 2007 Volumen 16, 2006 Volumen 15, 2005 Volumen 14, 2004 Volumen 13, 2003 Volumen 12, 2002 Volumen 11, 2001 Volumen 10, 2000 Volumen 9, 1999 Volumen 8, 1998 Volumen 7, 1997 Volumen 6, 1996 Volumen 5, 1995 Volumen 4, 1994

Critical Reviews™ in Eukaryotic Gene Expression

DOI: 10.1615/CritRevEukaryotGeneExpr.2020031020
pages 137-151

Angiogenesis-Centered Molecular Cross-Talk in Amyotrophic Lateral Sclerosis Survival: Mechanistic Insights

Keshav Thakur
Neuroscience Research Lab, Post Graduate Institute of Medical Education and Research, Chandigarh, India; Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India
Abha Tiwari
Neuroscience Research Lab, Post Graduate Institute of Medical Education and Research, Chandigarh, India
Kaushal Sharma
Neuroscience Research Lab, Post Graduate Institute of Medical Education and Research, Chandigarh, India; Centre for Systems Biology and Bioinformatics, Panjab University, Chandigarh, India
Shweta Modgil
Neuroscience Research Lab, Post Graduate Institute of Medical Education and Research, Chandigarh, India
Radhika Khosla
Neuroscience Research Lab, Post Graduate Institute of Medical Education and Research, Chandigarh, India
Akshay Anand
Neuroscience Research Lab, Post Graduate Institute of Medical Education and Research, Chandigarh, India


Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized with progressive muscle atrophy. We have attempted to establish the link between angiogenesis and cellular survival in the pathogenesis of ALS by compiling evidence described in various scientific reports. The phenotypes of human ALS have earlier been captured in the mutant SOD1 mice as well as by targeted deletion of the hypoxia response element (HRE) from the promoter of the mouse gene for vascular endothelial growth factor (VEGF). Indirect evidence shows that angiogenesis can help prevent oxidative stress, and hence, enhance cell survival. VEGF and angiogenin chiefly regulate the process of angiogenesis. Transactive response DNA-binding protein 43 (TDP-43) is usually found inside the nucleus, but in large number of cases of ALS, it accumulates in the cytoplasm (TDP-43 proteinopathy). Interestingly, TDP-43 proteinopathy is found to be aggravated in the presence of the OPTN mutation, which is the genetic factor that is responsible for such accumulation. Interaction of TDP-43 with progranulin can further affect the angiogenesis in ALS patients by regulating activity of VEGF receptors, but conclusive evidence is needed to establish its role in pathogenesis of ALS. Certain mutations in UBQLN2 and UBQLN4 indicate that ubiquitination has a role in ALS pathobiology, but its link to angiogenesis has not been adequately studied. Recent studies have shown that several mutations in RNA-binding proteins (RBPs) can also cause ALS. Conclusively, in this review, we have attempted to argue the role of angiogenesis in enhanced ALS survival rate is probably regulated with the activation of NF-κβ. Additionally, interaction between OPTN and TDP-43 can also impact the transcription of various angiogenic molecules. Whether targeting angiogenic substances or TDP-43 can provide clues about extending ALS survival rate, in combination with current treatments, can only be evaluated after additional studies.


  1. Aran F. Research on an as yet undescribed disease of the muscular system (progressive muscular atrophy). Arch Gen Med. 1848;24:15-35.

  2. Charcot JM. Lectures on the diseases of the nervous system. Delivered at La Salpetriene: London: New Sydenham Society; 1877.

  3. Chio A, Benzi G, Dossena M, Mutani R, Mora G. Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain. 2005;128(Pt 3):472-6.

  4. Armon C. Sports and trauma in amyotrophic lateral sclerosis revisited. J Neurol Sci. 2007;262(1-2):45-53.

  5. Andersen PM, Al-Chalabi A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol. 2011;7(11):603-15.

  6. Jacobsson J, Jonsson PA, Andersen PM, Forsgren L, Marklund SL. Superoxide dismutase in CSF from amyotrophic lateral sclerosis patients with and without CuZn-superoxide dismutase mutations. Brain. 2001 ;1 424(7):1461-6.

  7. Simpson E, Henry Y, Henkel J, Smith R, Appel SH. Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden. Neurology. 2004;62(10):1758-65.

  8. Storkebaum E, Quaegebeur A, Vikkula M, Carmeliet P. Cerebrovascular disorders: molecular insights and thera-peutic opportunities. Nat Neurosci. 2011;14(11):1390-7.

  9. Gupta PK, Prabhakar S, Sharma S, Anand A. Vascular endothelial growth factor-A (VEGF-A) and chemokine ligand-2 (CCL2) in amyotrophic lateral sclerosis (ALS) patients. J Neuroinflammation. 2011;8(1):47.

  10. Gupta PK, Prabhakar S, Abburi C, Sharma NK, Anand A. Vascular endothelial growth factor-A and chemokine ligand (CCL2) genes are upregulated in peripheral blood mononuclear cells in Indian amyotrophic lateral sclerosis patients. J Neuroinflammation. 2011;8(1):114.

  11. Gupta PK, Prabhakar S, Sharma NK, Anand A. Possible association between expression of chemokine receptor-2 (CCR2) and amyotrophic lateral sclerosis (ALS) patients of North India. PLoS One. 2012;7(6):e38382.

  12. Raab S, Beck H, Gaumann A, Yuce A, Gerber H-P, Plate K, Hammes H-P, Ferrara N, Breier G. Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor. Thromb Haemost. 2004;91(03):595-605.

  13. Ogunshola OO, Stewart WB, Mihalcik V, Solli T, Madri JA, Ment LR. Neuronal VEGF expression correlates with angiogenesis in postnatal developing rat brain. Develop Brain Res. 2000;119(1):139-53.

  14. Carmeliet P, Ruiz de Almodovar C. VEGF ligands and receptors: implications in neurodevelopment and neuro-degeneration. Cell Mol Life Sci. 2013;70(10):1763-78.

  15. Bautch VL, James JM. Neurovascular development: the beginning of a beautiful friendship. Cell Adh Migr. 2009;3(2):199-204.

  16. Lambrechts D, Storkebaum E, Morimoto M, Del-Favero J, Desmet F, Marklund SL, Wyns S, Thijs V, Andersson J, van Marion I, Al-Chalabi A, Borrnes S, Musson R, Hansen V, Beckman L, Adolfsson R, Pall HS, Prats H, Vermiere S, Rutgeerts P, Katayama S, Awata T, Leigh N, Lang-Lazdunski L, Dewerchin M, Shaw C, Moons L, Vlietinck R, Morrison KE, Robberecht W, Van Broeckhoven C, Collen D, Andersen PM, Carmeliet P. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet. 2003;34(4):383-94.

  17. Lambrechts D, Carmeliet P. VEGF at the neurovascular interface: therapeutic implications for motor neuron disease. Biochim Biophys Acta. 2006;1762(11-12):1109-21.

  18. Kishimoto K, Liu S, Tsuji T, Olson KA, Hu G-F. Endogenous angiogenin in endothelial cells is a general requirement for cell proliferation and angiogenesis. Oncogene. 2005;24(3):445-56.

  19. Greenway MJ, Andersen PM, Russ C, Ennis S, Cashman S, Donaghy C, Patterson V, Swingler R, Kieran D, Prehn J, Morrison KE, Green A, Acharya KR, Brown Jr RH, Hardimon O. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nat Genet. 2006;38(4):411-3.

  20. Fernandez-Santiago R, Hoenig S, Lichtner P, Sperfeld A-D, Sharma M, Berg D, Weichenrieder O, Illig T, Eger K, Meyer T, Anneser J, Munch C, Zierz S, Gasser T, Ludolph A. Identification of novel Angiogenin (ANG) gene missense variants in German patients with amyotrophic lateral sclerosis. J Neurol. 2009;256(8):1337-42.

  21. Paubel A, Violette J, Amy M, Praline J, Meininger V, Camu W, Corcia P, Andres CR, Vourc'h P; French Amyotrophic Lateral (ALS) Study Group. Mutations of the ANG gene in French patients with sporadic amyotrophic lateral sclerosis. Arch Neurol. 2008;65(10):1333-6.

  22. Gellera C, Tiloca C, Del Bo R, Corrado L, Pensato V, Agostini J, Cereda C, Ratti A, Castellotti B, Corti S, Bagarotti A, Cagnin A, Milani P, Gabelli C, Riboldi G, Mazzini L, Soraru G, D'Alfonso S, Taroni F, Comi GP, Ticozzi N, Silani V; SLAGEN Consortium. Ubiquilin 2 mutations in Italian patients with amyotrophic lateral sclerosis and frontotemporal dementia. J Neurol Neurosurg Psych. 2013;84(2):183-7.

  23. Gellera C, Colombrita C, Ticozzi N, Castellotti B, Bragato C, Ratti A, Taroni F, Silani V. Identification of new ANG gene mutations in a large cohort of Italian patients with amyotrophic lateral sclerosis. Neurogenetics. 2008;9(1):33-40.

  24. Conforti FL, Sprovieri T, Mazzei R, Ungaro C, La Bella V, Tessitore A, Patitucci A, Magariello A, Gabriele AL, Tedeschi G, Simone IL, Majorana G, Valentino P, Condino F, Bono F, Monsurro MR, Muglia M, Quattrone A. A novel Angiogenin gene mutation in a sporadic patient with amyotrophic lateral sclerosis from southern Italy. Neuromuscul Disord. 2008;18(1):68-70.

  25. Bhutani H, Anand A. Biomarkers in amyotrophic lateral sclerosis: is there a neurovascular pathway? Curr Neurovasc Res. 2012;9(4):302-9.

  26. Storkebaum E, Lambrechts D, Carmeliet P. VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection. Bioessays. 2004;26(9):943-54.

  27. Gao X, Xu Z. Mechanisms of action of angiogenin. Acta Biochim Biophys Sin (Shanghai). 2008;40(7):619-24.

  28. Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K, Van Dorpe J, Hellings P, Gorselink M, Heymans S. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet. 2001;28(2):131-8.

  29. Subramanian V, Crabtree B, Acharya KR. Human angiogenin is a neuroprotective factor and amyotrophic lateral sclerosis associated angiogenin variants affect neurite extension/pathfinding and survival of motor neurons. Hum Mol Genet. 2008;17(1):130-49.

  30. Krussel JS, Casan EM, Raga F, Hirchenhain J, Wen Y, Huang H-Y, Bielfeld P, Polan ML. Expression of mRNA for vascular endothelial growth factor transmembraneous receptors Flt1 and KDR, and the soluble receptor sflt in cycling human endometrium. Mol Hum Reproduct. 1999;5(5):452-8.

  31. Birkenhager R, Schneppe B, Rockl W, Wilting J, Weich HA, Mccarthy JE. Synthesis and physiological activity of heterodimers comprising different splice forms of vascular endothelial growth factor and placenta growth factor. Biochem J. 1996;316(Pt 3):703-7.

  32. Park JE, Chen HH, Winer J, Houck KA, Ferrara N. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem. 1994;269(41):25646-54.

  33. Ahmad S, Hewett PW, Al-Ani B, Sissaoui S, Fujisawa T, Cudmore MJ, Ahmed A. Autocrine activity of soluble Flt-1 controls endothelial cell function and angiogenesis. Vasc Cell. 2011;3(1):15.

  34. Anand A, Gupta P, Sharma N, Prabhakar S. Soluble VEGFR1 (sVEGFR1) as a novel marker of amyotrophic lateral sclerosis (ALS) in the North Indian ALS patients. Eur J Neurol. 2012;19(5):788-92.

  35. Kishikawa H, Wu D, Hu G-F. Targeting angiogenin in therapy of amyotropic lateral sclerosis. Expert Opin Ther Targets. 2008;12(10):1229-42.

  36. Li B, Xu W, Luo C, Gozal D, Liu R. VEGF-induced activation of the PI3-K/Akt pathway reduces mutant SOD1-mediated motor neuron cell death. Mol Brain Res. 2003;111(1-2):155-64.

  37. Romashkova JA, Makarov SS. NF-KB is a target of AKT in anti-apoptotic PDGF signalling. Nature. 1999; 401(6748):86-90.

  38. Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2006;351(3):602-11.

  39. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, MacKenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130-3.

  40. Winton MJ, Igaz LM, Wong MM, Kwong LK, Trojanowski JQ, Lee VM-Y. Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation. J Biol Chem. 2008;283(19):13302-9.

  41. Grossman M, Wood EM, Moore P, Neumann M, Kwong L, Forman MS, Clark CM, McCluskey LF, Miller BL, Lee VM-Y, Trojanowski JQ. TDP-43 pathologic lesions and clinical phenotype in frontotemporal lobar degeneration with ubiquitin-positive inclusions. Arch Neurol. 2007;64(10):1449-54.

  42. Gitcho MA, Baloh RH, Chakraverty S, Mayo K, Norton JB, Levitch D, Hatanpaa KJ, White III CL, Bigio EH, Caselli R, Baker M, Al-Lozi MT, Morris JC, Pestronk A, Rademakers R, Goate AM, Cairns NJ. TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol. 2008;63(4):535-8.

  43. Kabashi E, Valdmanis PN, Dion P, Spiegelman D, Mc-Conkey BJ, Velde CV, Bouchard J-P, Lacomblez L, Pochigaeva K, Salachas F, Pradat PF, Camu W, Meininger V, Dupre N, Rouleau GA. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet. 2008;40(5):572-4.

  44. Van Deerlin VM, Leverenz JB, Bekris LM, Bird TD, Yuan W, Elman LB, Clay D, Wood EM, Chen-Plotkin AS, Martinez-Lage M, Steinbart E, McCluskey L, Grossman M, Neumann M, Wu IL, Yang WS, Kalb R, Galasko DR, Montine TJ, Trojanowski JQ, Lee VM, Schellenberg GD, Yu CE. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008;7(5):409-16.

  45. 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. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008;319(5870):1668-72.

  46. Yokoseki A, Shiga A, Tan CF, Tagawa A, Kaneko H, Koyama A, Eguchi H, Tsujino A, Ikeuchi T, Kakita A, Okamoto K, Nishizawa M, Takahashi H, Onadera O. TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol. 2008;63(4):538-42.

  47. Wegorzewska I, Bell S, Cairns NJ, Miller TM, Baloh RH. TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A. 2009;106(44):18809-14.

  48. Wils H, Kleinberger G, Janssens J, Pereson S, Joris G, Cuijt I, Smits V, Ceuterick-de Groote C, Van Broeckhoven C, Kumar-Singh S. TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A. 2010;107(8):3858-63.

  49. Wang P, Wander CM, Yuan C-X, Bereman MS, Cohen TJ. Acetylation-induced TDP-43 pathology is suppressed by an HSF1-dependent chaperone program. Nat Commun. 2017;8(1):82.

  50. Butovsky O, Siddiqui S, Gabriely G, Lanser AJ, Dake B, Murugaiyan G, Doykan CE, Wu PM, Gali RR, Iyer LK, Lawson R, Berry J, Krichevsky AM, Cudkowicz ME, Weiner HL. Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J Clin Invest. 2012;122(9):3063-87.

  51. Sako W, Ito H, Yoshida M, Koizumi H, Kamada M, Fujita K, Hashizume Y, Izumi Y, Kaji R. Nuclear factor KB expression in patients with sporadic amyotrophic lateral sclerosis and hereditary amyotrophic lateral sclerosis with optineurin mutations. Clin Neuropathol. 2012;31(6): 418-23.

  52. Cicardi ME, Cristofani R, Rusmini P, Meroni M, Ferrari V, Vezzoli G, Tedesco B, Piccolella M, Messi E, Galbiati M, Boncoraglio A, Carra S, Crippa V, Poletti A. Tdp-25 routing to autophagy and proteasome ameliorates its aggregation in amyotrophic lateral sclerosis target cells. Sci Rep. 2018;8(1):12390.

  53. Seilhean D, Cazeneuve C, Thuries V, Russaouen O, Millecamps S, Salachas F, Meininger V, LeGuern E, Duyckaerts C. Accumulation of TDP-43 and a-actin in an amyotrophic lateral sclerosis patient with the K17I ANG mutation. Acta Neuropathol. 2009;118(4):561-73.

  54. Yamasaki S, Ivanov P, Hu G-F, Anderson P. Angiogenin cleaves tRNA and promotes stress-induced translational repression. J Cell Biol. 2009;185(1):35-42.

  55. Colombrita C, Onesto E, Megiorni F, Pizzuti A, Baralle FE, Buratti E, Silani V, Ratti A. TDP-43 and FUS RNA-binding proteins bind distinct sets of cytoplasmic messenger RNAs and differently regulate their post-transcriptional fate in motoneuron-like cells. J Biol Chem. 2012;287(19):15635-47.

  56. Irwin D, Lippa C, Rosso A. Progranulin (PGRN) expression in ALS: an immunohistochemical study. J Neurol Sci. 2009;276(1-2):9-13.

  57. Eguchi R, Nakano T, Wakabayashi I. Progranulin and granulin-like protein as novel VEGF-independent angiogenic factors derived from human mesothelioma cells. Oncogene. 2017;36(5):714-22.

  58. Chang MC, Srinivasan K, Friedman BA, Suto E, Modrusan Z, Lee WP, Kaminker JS, Hansen DV, Sheng M. Progranulin deficiency causes impairment of autophagy and TDP-43 accumulation. J Exp Med. 2017;214(9):2611-28.

  59. Feneberg E, Steinacker P, Volk AE, Weishaupt JH, Wollmer MA, Boxer A, Tumani H, Ludolph AC, Otto M. Progranulin as a candidate biomarker for therapeutic trial in patients with ALS and FTLD. J Neural Transm (Vienna). 2016;123(3):289-96.

  60. Tangkeangsirisin W, Serrero G. PC cell-derived growth factor (PCDGF/GP88, progranulin) stimulates migration, invasiveness and VEGF expression in breast cancer cells. Carcinogenesis. 2004;25(9):1587-92.

  61. Kumar-Singh S. Progranulin and TDP-43: mechanistic links and future directions. J Mol Neurosci. 2011;45(3): 561-73.

  62. Ugarte F, Forsberg EC. Haematopoietic stem cell niches: new insights inspire new questions. EMBO J. 2013; 32(19):2535-47.

  63. Berson A, Sartoris A, Nativio R, Van Deerlin V, Toledo JB, Porta S, Liu S, Chung C-Y, Garcia BA, Lee VM-Y, Trojanowski JQ, Johnson FB, Berger SL, Bonini NM. TDP-43 promotes neurodegeneration by impairing chromatin remodeling. Curr Biol. 2017;27(23):3579-90. e6.

  64. Gomez-Del Arco P, Perdiguero E, Yunes-Leites PS, Acm-Perez R, Zeini M, Garcia-Gomez A, Sreenivasan K, Jimenez-Alcazar M, Segales J, Lopez-Maderuelo D, Ornes B, Jimenez-Borreguero LJ, D'Amato G, Enshell-Seijffers D, Morgan B, Georgopoulos K, Islam AB, Braun T, de la Pompa JL, Kim J, Enriquez JA, Ballestar E, Munoz-Canoves P, Redondo JM. The chromatin remodeling complex Chd4/NuRD controls striated muscle identity and metabolic homeostasis. Cell Metab. 2016;23(5):881-92.

  65. Arany Z, He H, Lin J, Hoyer K, Handschin C, Toka O, Ahmad F, Matsui T, Chin S, Wu P-H, Rybkin II, Shelton JM, Manieri M, Cinti S, Schoen FJ, Bassel-Duby R, Rosenzweig A, Ingwall JS, Spiegelman BM. Tran-scriptional coactivator PGC-1a controls the energy state and contractile function of cardiac muscle. Cell Metab. 2005;1(4):259-71.

  66. 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. Mutations of optineurin in amyotrophic lateral sclerosis. Nature. 2010;465(7295):223-6.

  67. Deng H-X, Bigio EH, Zhai H, Fecto F, Ajroud K, Shi Y, Yan J, Mishra M, Ajroud-Driss S, Heller S, Sufit R, Siddique N, Mugnaini E, Siddique T. Differential involvement of optineurin in amyotrophic lateral sclerosis with or with-out SOD1 mutations. Arch Neurol. 2011;68(8):1057-61.

  68. Nagabhushana A, Bansal M, Swarup G. Optineurin is required for CYLD-dependent inhibition of TNFa-induced NF-KB activation. PLoS One. 2011;6(3):e17477.

  69. Swarup G, Nagabhushana A. Optineurin, a multifunctional protein involved in glaucoma, amyotrophic lateral sclerosis and antiviral signalling. J Biosci. 2010;35(4):501-5.

  70. Wu D, Yu W, Kishikawa H, Folkerth RD, Iafrate AJ, Shen Y, Xin W, Sims K, Hu GF. Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis. Ann Neurol. 2007;62(6):609-17.

  71. Lee EB, Lee VM-Y, Trojanowski JQ. Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci. 2011;13(1):38-50.

  72. Freischmidt A, Wieland T, Richter B, Ruf W, Schaeffer V, Muller K, Marroquin N, Nordin F, Hubers A, Weydt P, Pinto S, Press R, Millecamps S, Molko N, Bernard E, Desnuelle C, Soriani MH, Dorst J, Graf E, Nordstrom U, Feiler MS, Putz S, Boeckers TM, Meyer T, Winkler AS, Winkelman J, de Carvajho M, Thal DR, Otto M, Brannstrom T, Volk AE, Kursula P, Danzer KM, Lichtner P, Dikic I, Meitinger T, Ludolph AC, Strom TM, Andersen PM, Weishaupt JH. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci. 2015;18(5):631-6.

  73. Wong YC, Holzbaur EL. Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc Natl Acad Sci U S A. 2014;111(42):E4439-E48.

  74. Richter B, Sliter DA, Herhaus L, Stolz A, Wang C, Beli P, Zaffagnini G, Wild P, Martens S, Wagner SA, Youle RJ, Dikic I. Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. Proc Natl Acad Sci U S A. 2016;113(15):4039.

  75. Kwok CT, Morris A, de Belleroche JS. Sequestosome-1 (SQSTM1) sequence variants in ALS cases in the UK: prevalence and coexistence of SQSTM1 mutations in ALS kindred with PDB. Eur J Hum Genet. 2014;22(4):492-6.

  76. Goode A, Rea S, Sultana M, Shaw B, Searle MS, Layfield R. ALS-FTLD associated mutations of SQSTM1 impact on Keap1-Nrf2 signalling. Mol Cell Neurosci. 2016;76:52-8.

  77. Goode A, Butler K, Long J, Cavey J, Scott D, Shaw B, Sollenberger J, Gell C, Johansen T, Oldham NJ, Searle MS, Layfield R. Defective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLD. Autophagy. 2016;12(7):1094-104.

  78. Czabanka M, Korherr C, Brinkmann U, Vajkoczy P. Influence of TBK-1 on tumor angiogenesis and microvascular inflammation. Front Biosci. 2008;13:7243-9.

  79. Korherr C, Gille H, Schafer R, Koenig-Hoffmann K, Dixelius J, Egland KA, Pastan I, Brinkmann U. Identification of proangiogenic genes and pathways by high-throughput functional genomics: TBK1 and the IRF3 pathway. Proc Natl Acad Sci U S A. 2006;103(11):4240-5.

  80. de Majo M, Topp SD, Smith BN, Nishimura AL, Chen H-J, Gkazi AS, Miller J, Wong CH, Vance C, Baas F, Ten Asbroek ALMA, Kenna KP, Ticozzi N, Redondo AG, Esteban-Perez J, Tiloca C, Verde F, Duga S, Morrison KE, Shaw PJ, Kirby J, Turner MR, Talbot K, Hardiman O, Glass JD, de Belleroche J, Gellera C, Ratti A, Al-Chalabi A, Brown RH, Silani V, Landers JE, Shaw CE. ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function. Neurobiol Aging. 2018;71:266.

  81. van der Zee J, Gijselinck I, Van Mossevelde S, Perrone F, Dillen L, Heeman B, Baumer V, Engelborghs S, De Bleecker J, Baets J, Gelpi E, Rojas-Garcia R, Clarimon J, Lleo A, Diehl-Schmid J, Alexopoulos P, Perneczky R, Synofzik M, Just J, Schols L, Graff C, Thonberg H, Borroni B, Padovani A, Jordanova A, Sarafov S, Tournev I, de Medonja A, Miltenberger-Miltenyi G, Simoes do Couto F, Ramirez A, Jessen F, Heneka MT, Gomez-Tortosa E, Danek A, Cras P, Vandenberghe R, De Jonghe P, De Deyn PP, Sleegers K, Cruts M, Van Broeckhoven C, Goeman J, Nuytten D, Smets K, Robberecht W, Damme PV, Bleecker J, Santens P, Dermaut B, Versijpt J, Michotte A, Ivanoiu A, Deryck O, Bergmans B, Delbeck J, Bruyland M, Willems C, Salmon E, Pastor P, Ortega-Cubero S, Benussi L, Ghidoni R, Binetti G, Hernandez I, Boada M, Ruiz A, Sorbi S, Nacmias B, Bagnoli S, Sorbi S, Sanchez-Valle R, Llado A, Santana I, Rosario Almeida M, Frisoni GB, Maetzler W, Matej R, Fraidakis MJ, Kovacs GG, Fabrizi GM, Testi S. TBK1 mutation spectrum in an extended European patient cohort with frontotemporal dementia and amyotrophic lateral sclerosis. Hum Mutat. 2017;38(3):297-309.

  82. Oakes JA, Davies MC, Collins MO. TBK1: a new player in ALS linking autophagy and neuroinflammation. Mol Brain. 2017;10(1):5.

  83. Mrak RE, Griffin WST. Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging. 2005;26(3): 349-54.

  84. Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW. Onset and progression in inherited ALS determined by motor neurons and microglia. Science. 2006;312(5778):1389-92.

  85. O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA-155 is induced during the macro-phage inflammatory response. Proc Natl Acad Sci U S A. 2007;104(5):1604-9.

  86. Yin F, Banerjee R, Thomas B, Zhou P, Qian L, Jia T, Ma X, Ma Y, Iadecola C, Beal MF, Nathan C, Ding A. Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med. 2010;207(1):117-28.

  87. Liu-Yesucevitz L, Bilgutay A, Zhang Y-J, Vanderwyde T, Citro A, Mehta T, Zaarur N, McKee A, Bowser R, Sherman M, Petrucelli L, Wolozin B. Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue. PLoS One. 2010;5(10):e13250.

  88. Mosley RL, Gendelman HE. Control of neuroinflammation as a therapeutic strategy for amyotrophic lateral sclerosis and other neurodegenerative disorders. Exp Neurol. 2010;222(1):1-5.

  89. Muessel MJ, Klein RM, Wilson AM, Berman NE. Ablation of the chemokine monocyte chemoattractant protein-1 delays retrograde neuronal degeneration, attenuates microglial activation, and alters expression of cell death molecules. Brain Res Mol Brain Res. 2002;103(1-2):12-27.

  90. Henkel JS, Engelhardt JI, Siklos L, Simpson EP, Kim SH, Pan T, Goodman JC, Siddique T, Beers DR, Appel SH. Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol. 2004;55(2):221-35.

  91. Maihofner C, Probst-Cousin S, Bergmann M, Neuhuber W, Neundorfer B, Heuss D. Expression and localization of cyclooxygenase-1 and -2 in human sporadic amyotrophic lateral sclerosis. Eur J Neurosci. 2003;18(6):1527-34.

  92. Spliet WG, Aronica E, Ramkema M, Aten J, Troost D. Increased expression of connective tissue growth factor in amyotrophic lateral sclerosis human spinal cord. Acta Neuropathol. 2003;106(5):449-57.

  93. Malessa S, Leigh PN, Bertel O, Sluga E, Hornykiewicz O. Amyotrophic lateral sclerosis: glutamate dehydrogenase and transmitter amino acids in the spinal cord. J Neurol Neurosurg Psychiatry. 1991;54(11):984-8.

  94. Lu L, Wang S, Zheng L, Li X, Suswam EA, Zhang X, Wheeler CG, Nabors L, Filippova N, King PH. Amyotrophic lateral sclerosis-linked mutant SOD1 sequesters Hu antigen R (HuR) and TIA-1-related protein (TIAR). Implications for impaired post-transcriptional regulation of vascular endothelial growth factor. J Biol Chem. 2009;284(49):33989-98.

  95. Lunn JS, Sakowski SA, Kim B, Rosenberg AA, Feldman EL. Vascular endothelial growth factor prevents G93A-SOD1-induced motor neuron degeneration. Dev Neurobiol. 2009;69(13):871-84.

  96. Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, Lacas-Gervais S, Fragaki K, Berg-Alonso L, Kageyama Y, Serre V, Moore DG, Verschueren A, Rouzier C, Le Bar I, Auge G, Cochaud C, Lespinasse F, N'Guyen K, de Septenville A, Brice A, Yu-Wai-Man P, Sesaki H, Pouget J, Paquis-Flucklinger V. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain. 2014;137(Pt 8):2329-45.

  97. Purandare N, Somayajulu M, Huttemann M, Grossman LI, Aras S. The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): partners in mitochondrial and nuclear function and dysfunction. J Biol Chem. 2018;293(17):6517-29.

  98. Brenner D, Muller K, Wieland T, Weydt P, Bohm S, Lule D, Hubers A, Neuwirth C, Weber M, Borck G, Wahlqvist M, Danzer KM, Volk AE, Meitinger T, Strom TM, Otto M, Kassubek J, Ludolph AC, Andersen PM, WeisHaupt JH. NEK1 mutations in familial amyotrophic lateral sclerosis. Brain. 2016;139(Pt 5):e28.

  99. Fang X, Lin H, Wang X, Zuo Q, Qin J, Zhang P. The NEK1 interactor, C21ORF2, is required for efficient DNA damage repair. Acta Biochim Biophys Sin. 2015;47(10):834-41.

  100. Kenna KP, Van Doormaal PT, Dekker AM, Ticozzi N, Kenna BJ, Diekstra FP, Van Rheenen W, Van Eijk KR, Jones AR, Keagle P. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nat Genet. 2016;48(9):1037-42.

  101. Patil M, Pabla N, Huang S, Dong Z. Nek1 phosphorylates Von Hippel-Lindau tumor suppressor to promote its prote-asomal degradation and ciliary destabilization. Cell Cycle. 2013;12(1):166-71.

  102. Ruf M, Mittmann C, Nowicka AM, Hartmann A, Hermanns T, Poyet C, van den Broek M, Sulser T, Moch H, Schraml P. pVHL/HIF-regulated CD70 expression is associated with infiltration of CD27+ lymphocytes and increased serum levels of soluble CD27 in clear cell renal cell carcinoma. Clin Cancer Res. 2015;21(4):889-98.

  103. Haase VH. The VHL tumor suppressor: master regulator of HIF. Curr Pharm Des. 2009;15(33):3895-903.

  104. Van Rheenen W, Shatunov A, Dekker AM, McLaughlin RL, Diekstra FP, Pulit SL, Van Der Spek RA, Vosa U, De Jong S, Robinson MR, Yang J, Fogh I, van Doormaal PT, Tazelaar GH, Koppers M, Biokhuis AM, Sproviero W, Jones AR, Kenna KP, van Eijk KR, Harschnitz O, Schellevis RD, Brands WJ, Medic J, Menelaou A, Vajda A, Ticozzi N, Lin K, Rogelj B, Vrabec K, Ravnik-Glavac M, Koritnik B, Zidar J, Leonardis L, Groselj LD, Millecamps S, Salachas F, Meininger V, de Carvalho M, Pinto S, Mora JS, Rojas-Garcia R, Polak M, Chandran S, Colville S, Swingler R, Morrison KE, Shaw PJ, Hardy J, Orrell RW, Pittman A, Sidle K, Fratta P, Malaspina A, Topp S, Petri S, Abdulla S, Drepper C, Sendtner M, Meyer T, Ophoff RA, Staats KA, Wiedau-Pazos M, Lomen-Hoerth C, Van Deerlin VM, Trojanowski JQ, Elman L, McCluskey L, Basak AN, Tunca C, Hamzeiy H, Parman Y, Meitinger T, Lichtner P, Radivojkov-Blagojevic M, Andres CR, Maurel C, Bensimon G, Landwehrmeyer B, Brice A, Payan CA, Saker-Delye S, Durr A, Wood NW, Tittmann L, Lieb W, Franke A, ietschel M, Cichon S, Nothen MM, Amouyel P, Tzourio C, Dartigues JF, Uitterlinden AG, Rivadeneira F, Estrada K, Hofman A, Curtis C, Blauw HM, van der Kool AJ, de Visser M, Goris A, Weber M, Shaw CE, Smith BN, Pansarasa O, Cereda C, Del Bo R, Comi GP, D'Alfonso S, Bertolin C, Soraru G, Mazzini L, Pensato V, Gellera C, Tiloca C, Ratti A, Calvo A, Moglia C, Brunetti M, Arcuti S, Capozzo R, Zecca C, Lunetta C, Penco S, Riva N, Padovani A, Filosto M, Muller B, Stuit RJ; PARALS Registry; SLALOM Group; SLAP Registry; FALS Sequencing Consortium; SLAGEN Consortium; NNIPPS Study Group, Blair I, Zhang K, McCann EP, Fifita JA, Nicholson GA, Rowe DB, Pamphlett R, Kiernan MC, Grosskreutz J, Witte OW, Ringer T, Prell T, Stubendorff B, Kurth I, Hubmer CA, Leigh PN, Casale F, Chio A, Beghi E, Pupillo E, Tortelli R, Logroscino G, Powell J, Ludolph AC, Weishaupt JH, Robberecht W, Van Damme P, Franke L, Pers TH, Brown RH, Glass JD, Landers JE, Hardiman O, Andersen PM, Corcia P, Vourc'h P, Silani V, Wray NR, Visscher PM, de Bakker PI, van Es MA, Pasterkamp RJ, Lewis CM, Breen G, Al-Chalabi A, van den Berg LH, Veldink JH. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nat Genet. 2016;48(9):1043-8.

  105. Le NT, Chang L, Kovlyagina I, Georgiou P, Safren N, Braunstein KE, Kvarta MD, Van Dyke AM, LeGates TA, Philips T, Morrison BM, Thompson SM, Puche AC, Gould TD, Rothstein JD, Wong PC, Monteiro MJ. Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations. Proc Natl Acad Sci U S A. 2016;113(47):E7580-E9.

  106. Fahed AC, McDonough B, Gouvion CM, Newell KL, Dure LS, Bebin M, Bick AG, Seidman JG, Harter DH, Seidman CE. UBQLN2 mutation causing heterogeneous X-linked dominant neurodegeneration. Ann Neurol. 2014;75(5):793-8.

  107. Williams KL, Warraich ST, Yang S, Solski JA, Fernando R, Rouleau GA, Nicholson GA, Blair IP. UBQLN2/ubiquilin 2 mutation and pathology in familial amyotrophic lateral sclerosis. Neurobiol Aging. 2012;33(10):2527.e3-10.

  108. Edens BM, Yan J, Miller N, Deng H-X, Siddique T, Ma YC. A novel ALS-associated variant in UBQLN4 regulates motor axon morphogenesis. Elife. 2017;6:e25453.

  109. Bakkar N, Kovalik T, Lorenzini I, Spangler S, Lacoste A, Sponaugle K, Ferrante P, Argentinis E, Sattler R, Bowser R. Artificial intelligence in neurodegenerative disease research: use of IBM Watson to identify additional RNA-binding proteins altered in amyotrophic lateral sclerosis. Acta Neuropathol. 2018;135(2):227-47.

  110. Munch C, Sedlmeier R, Meyer T, Homberg V, Sperfeld A, Kurt A, Prudlo J, Peraus G, Hanemann C, Stumm G, Ludolph AC. Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS. Neurology. 2004;63(4): 724-6.

Articles with similar content:

Nitrosothiol Signaling in Anoikis Resistance and Cancer Metastasis
Forum on Immunopathological Diseases and Therapeutics, Vol.3, 2012, issue 2
Neelam Azad, Anand Krishnan V. Iyer, Liying Wang, Sudjit Luanpitpong, Yon Rojanasakul
Myb-lnduced Transformation
Critical Reviews™ in Oncogenesis, Vol.7, 1996, issue 3-4
Linda Wolff
Type 2 Diabetes and Cancer: An Overview of Epidemiological Evidence and Potential Mechanisms
Critical Reviews™ in Oncogenesis, Vol.24, 2019, issue 3
Farhad Hosseinpanah, Asghar Ghasemi, Parvin Mirmiran, Zahra Bahadoran
Histone Acetyltransferases in Cancer: Guardians or Hazards?
Critical Reviews™ in Oncogenesis, Vol.22, 2017, issue 3-4
Antonis Kirmizis, Christina Demetriadou
Functional Role of MicroRNAs in Prostate Cancer and Therapeutic Opportunities
Critical Reviews™ in Oncogenesis, Vol.18, 2013, issue 4
Marcello Maugeri-Sacca, Valeria Coppola, Ruggero De Maria, Desiree Bonci