The role of autophagy: What can be learned from the genetic forms of amyotrophic lateral sclerosis

CNS and Neurological Disorders - Drug Targets

Volumn 9, Issue 3, 2010, Pages 268-278

  Pasquali, Livia ^a   Ruffoli, Riccardo ^a   Fulceri, Federica ^a   Pietracupa, Sara ^b   Siciliano, Gabriele ^a   Paparelli, Antonio ^a   Fornai, Francesco ^a,b  

^a UNIVERSITY OF PISA   (Italy)

^b IRCCS NEUROMED   (Italy)

Author keywords

Autophagosome; Frontotemporal dementia; Fused in sarcoma translated in liposarcoma; Genetics of amytrophic lateral sclerosis; Motor neuron; Tar dna binding protein 43; Ubiquitin proteasome system

Indexed keywords

ALS2 PROTEIN; BINDING PROTEIN; CARRIER PROTEIN; COPPER ZINC SUPEROXIDE DISMUTASE; DYNACTIN; DYNEIN ADENOSINE TRIPHOSPHATASE; ENDOSOMAL SORTING COMPLEX RESPONSIBLE FOR TRANSFER PROTEIN; FUSED IN SARCOMA TRANSLATED IN LIPOSARCOMA; GUANINE NUCLEOTIDE EXCHANGE FACTOR; MESSENGER RNA; NEUROFILAMENT PROTEIN; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEASOME; TAR DNA BINDING PROTEIN; UNCLASSIFIED DRUG;

AMINO ACID SEQUENCE; AMYOTROPHIC LATERAL SCLEROSIS; ARTICLE; AUTOPHAGY; CELL FUSION; CELL ORGANELLE; CELL SURVIVAL; FAMILIAL DISEASE; GENE MUTATION; GENETIC ASSOCIATION; HUMAN; MOLECULAR MECHANICS; MOTONEURON; NERVE CELL NECROSIS; NEUROPATHOLOGY; NONHUMAN; PATHOGENESIS; PROTEIN AGGREGATION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; SIGNAL TRANSDUCTION;

EID: 77954346346     PISSN: 18715273     EISSN: None     Source Type: Journal    
DOI: 10.2174/187152710791292594     Document Type: Article

References (143)

1. Rowland, L.P. Amyotrophic lateral sclerosis. Curr. Opin. Neurol., 1994, 7(4), 310-315.
2. Bruijn, L.I.; Miller, T.M.; Cleveland, D.W. Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu. Rev. Neurosci., 2004, 27, 723-749.
3. Cozzolino, M.; Ferri, A.; Carrì, M.T. Amyotrophic lateral sclerosis: from current developments in the laboratory to clinical implications. Antioxid. Redox. Signal., 2008, 10(3), 405-443.
4. Wijesekera, L.C.; Leighyang, P.N. Amyotrophic lateral sclerosis. Orphanet. J. Rare Dis., 2009, 4(3), doi:10.1186/1750-1172-4-3.
5. Rosen, D.R.; Siddique, T.; Patterson, D.; Figlewicz, D.A.; Sapp, P.; Hentati, A.; Donaldson, D.; Goto, J.; O'Regan, J.P.; Deng, H.X. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature, 1993, 362, 59-62.
6. Yang, Y.; Hentati, A.; Deng, H.X.; Dabbagh, O.; Sasaki, T.; Hirano, M.; Hung, W.Y.; Ouahchi, K.; Yan, J.; Azim, A.C.; Cole, N.; Gascon, G.; Yagmour, A.; Ben-Hamida, M.; Pericak-Vance, M.; Hentati, F.; Siddique, T. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat. Genet., 2001, 29(2), 160-165.
7. Chen, Y.Z.; Hashemi, S.H.; Anderson, S.K.; Huang, Y.; Moreira, M.C.; Lynch, D.R.; Glass, I.A.; Chance, P.F.; Bennett, C.L. Senataxin, the yeast Sen1p othologue: characterization of a unique protein in which recessive mutations cause ataxia and dominant mutations cause motor neuron disease. Neurobiol. Dis., 2006, 23, 97-108.
8. Zhao, Z.H.; Chen, W.Z.; Wu, Z.Y.; Wang, N.; Zhao, G.X.; Chen, W.J.; Murong, S.X. A novel mutation in senataxin gene identified in a Chinese patient with sporadic amyotrophic lateral sclerosis. Amyotroph. Lateral Scler., 2009, 10, 118-122.
9. Kwiatkowski, T.J. Jr.; Bosco, D.A.; Leclerc, A.L.; Tamrazian, E.; Vanderburg, C.R.; Russ, C.; Davis, A.; Gilchrist, J.; Kasarskis, E.J.; Munsat, T.; Valdmanis, P.; Rouleau, G.A.; Hosler, B.A.; Cortelli, P.; de Jong, P.J.; Yoshinaga, Y.; Haines, J.L.; Pericak-Vance, M.A.; Yan, J.; Ticozzi, N.; Siddique, T.; McKenna-Yasek, D.; Sapp, P.C.; Horvitz, H.R.; Landers, J.E.; Brown, R.H. Jr. Mutations inthe FUS/TLS geneonchromosome 16 cause familial amyotrophic lateral sclerosis. Science, 2009, 323, 1205-1208.
10. Vance, C.; Rogelj, B.; Hortobágyi, T.; De Vos, K.J.; Nishimura, A.L.; Sreedharan, J.; Hu, X.; Smith, B.; Ruddy, D.; Wright, P.; Ganesalingam, J.; Williams, K.L.; Tripathi, V.; Al-Saraj, S.; Al-Chalabi, A.; Leigh, P.N.; Blair, I.P.; Nicholson, G.; de Belleroche J.; Gallo, J.M.; Miller, C.C.; Shaw, C.E. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science, 2009, 323, 1208-1211.
11. Nishimura, A.L.; Mitne-Neto, M.; Silva, H.C.A.; Richieri-Costa, A.; Middleton, S.; Cascio D.; Kok, F.; Oliveira, J.R.; Gillingwater, T.; Webb, J.; Skehel, P.; Zatz, M. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am. J. Hum. Genet., 2004, 75, 822-831.
12. Nishimura, A.L.; Mitne-Neto, M.; Silva, H.C.A.; Oliveira, J.R.M.; Vainzof, M.; Zatz, M. A novel locus for late onset amyotrophic lateral sclerosis/motor neurone disease variant at 20q13. J. Med. Genet., 2004, 41, 315-320.
13. Greenway, M.J.; Alexander, M.D.; Ennis, S.; Traynor, B.J.; Corr, B.; Frost, E.; Green, A.; Hardiman, O. A novel candidate region for ALS on chromosome 14q11.2. Neurology, 2004, 63(10), 1936-1938.
14. Greenway, M.J.; Andersen, P.M.; Russ, C.; Ennis, S.; Cashman, S.; Donaghy, C.; Patterson, V.; Swingler, R.; Kieran, D.; Prehn, J.; Morrison, K.E.; Green, A.; Acharya, K.R.; Brown, R.H. Jr.; Hardiman, O. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nat. Genet., 2006, 38(4), 411-413.
15. 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.
16. Sreedharan, J.; Blair, I.P.; Tripathi, V.B.; Hu, X.; Vance, C.; Rogelj, B.; Ackerley, S.; Durnall, J.C.; Williams, K.L.; Buratti, E.; Baralle, F.; de Belleroche, J.; Mitchell, J.D.; Leigh, P.N.; Al-Chalabi, A.; Miller, C.C.; Nicholson, G.; Shaw, C.E. TDP-43mutations in familial and sporadic amyotrophic lateral sclerosis. Science, 2008, 319, 1668-1672.
17. Van Deerlin, V.M.; Leverenz, J.B.; Bekris, L.M.; Bird, T.D.; Yuan, W.; Elman, L.B.; Clay, D.; Wood, E.M.; Chen-Plotkin, A.S.; Martinez-Lage, M.; Steinbart, E.; McCluskey, L.; Grossman, M.; Neumann, M.; Wu, I.L.; Yang, W.S.; Kalb, R.; Galasko, D.R.; Montine, T.J.; Trojanowski, J.Q.; Lee, V.M.; Schellenberg, G.D.; Yu, C.E. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histological analysis. Lancet Neurol., 2008, 7(5), 409-416.
18. Kühnlein, P.; Sperfeld, A.D.; Vanmassenhove, B.; Van Deerlin, V.; Lee, V.M.Y.; Trojanowski, J.Q.; Kretzschmar, H.A.; Ludolph, A.C.; Neumann, M. Two German kindreds with familial amytrophic lateral sclerosis due to TARDBP mutations. Arch. Neurol., 2008, 65, 1185-1189.
19. Del Bo, R.; Grezzi, S.; Corti, S.; Pandolfo, M.; Ranieri, M.; Santoro, D.; Ghigne, I.; Pelle, A.; Orsetti, V.; Mancuso, M.; Sorarù, G.; Briani, C.; Angelici, C.; Siciliano, G.; Bresolin, N.; Comi, G.P. TARDBP (TDP-43) sequence analysis in patients with familial and sporadic ALS: identification of two novel mutations. Eur. J. Neurol., 2009, 16(6), 727-732.
20. Münch, C.; Sedlmeier, R.; Meyer, T.; Homberg, V.; Sperfeld, A.D.; Kurt, A.; Prudlo, J.; Peraus, G.; Hanemann, C.O.; Stumm, G.; Ludolph, A.C. Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS. Neurology, 2004, 63(4), 724-726.
21. Puls, I.; Jonnakuty, C.; LaMonte, B.H.; Holzbaur, E.L.; Tokito, M.; Mann, E.; Floeter, M.K.; Bidus, K.; Drayna, D.; Oh, S.J.; Brown, R.H. Jr.; Ludlow, C.L.; Fischbeck, K.H. Mutant dynactin in motor neuron disease. Nat. Genet., 2003, 33(4), 455-456.
22. Al-Chalabi, A.; Andersen, P.M.; Nilsson, P.; Chioza, B.; Andersson J.L.; Russ, C.; Shaw, C.E.; Powell, J.F.; Leigh, P.N. Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis. Hum. Molec. Genet., 1999, 8, 157-164.
23. Gros-Louis, F.; Larivière, R.; Gowing, G.; Laurent, S.; Camu, W.; Bouchard, J.P.; Meininger, V.; Rouleau, G.A.; Julien, J.P. A frameshift deletion in peripherin gene associated with amyotrophic lateral sclerosis. J. Biol. Chem., 2004, 279(44), 45951-45956.
24. Fornai, F.; Longone, P.; Cafaro, L.; Kastsiuchenka, O.; Ferrucci, M.; Manca, M.L.; Lazzeri, G.; Spalloni, A.; Bellio, N.; Lenzi, P.; Modugno, N.; Siciliano, G.; Isidoro, C.; Murri, L.; Ruggirei, S.; Paparelli, A. Lithium delays progression of amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA, 2008, 105(6), 2052-2057.
25. Fornai, F.; Longone, P.; Ferrucci, M.; Lenzi, P.; Isidoro, C.; Ruggieri, S.; Paparelli, A. Autophagy and amyotrophic lateral sclerosis: The multiple roles of lithium. Autophagy, 2008, 4(4), 527-530.
26. Rusten, T.E.; Simonsen, A. ESCRT functions in autophagy and associated disease. Cell Cycle, 2008, 7, 1166-1172.
27. Ferrucci, M.; Pasquali, L.; Paparelli, A.; Ruggieri, S.; Fornai, F. Pathways of methamphetamine toxicity. Ann. NY Acad. Sci., 2008, 1139, 177-185.
28. Pasquali, L.; Longone, P.; Isidoro, C.; Ruggieri, S.; Paparelli, A.; Fornai, F. Autophagy, lithium, and amyotrophic lateral sclerosis. Muscle Nerve, 2009, 40(2), 173-194.
29. Gal, J.; Ström, A.L.; Kwinter, D.M.; Kilty, R.; Zhang, J.; Shi, P.; Fu, W.; Wooten, M.W.; Zhu, H. Sequestosome 1/p62 links familial ALS mutant SOD1 to LC3 via an ubiquitin-independent mechanism. J. Neurochem., 2009, 111(4), 1062-1073.
30. Caccamo, A.; Majumder, S.; Deng, J.J.; Bai, Y.; Thornton, F.B.; Oddo, S. Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability. J. Biol. Chem., 2009, 284(40), 27416-27424.
31. Madeo, F.; Eisenberg, T.; Kroemer, G. Autophagy for the avoidance of neurodegeneration. Genes Dev., 2009, 23(19), 2253-2259.
32. Urushitani, M.; Sato, T.; Bamba, H.; Hisa, Y.; Tooyama, I. Synergistic effect between proteasome and autophagosome in the clearance of polyubiquitinated TDP-43. J. Neurosci. Res., 2010, 88(4), 784-797.
33. Matus, S.; Nassif, M.; Glimcher, L.H.; Hetz, C. XBP-1 deficiency in the nervous system reveals a homeostatic switch to activate autophagy. Autophagy, 2009, 5(8), 1226-1228.
34. Klionsky, D.J.; Emr, S.D. Autophagy as a regulated pathway of cellular degradation. Science, 2000, 290(5497), 1717-1721.
35. Mariño, G.; Lopez-Otin, C. Autophagy: molecular mechanism, physiological functions and relevance in human pathology. Cell Mol. Life Sci., 2004, 61, 1439-1454.
36. Hara, T.; Nakamura, K.; Matsui, M.; Yamamoto, A.; Nakahara, Y.; Suzuki-Migishima, R.; Yokoyama, M.; Mishima, K.; Saito, I.; Okano, H.; Mizushima, N. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature, 2006, 441(7095), 885-889.
37. Menzies, F.M.; Ravikumar, B.; Rubinsztein, D.C. Protective roles for induction of autophagy in multiple proteinopathies. Autophagy, 2006, 2(3), 224-225.
38. Rubinsztein, C.D.; Gestwicki, J.E.; Murphy L.O.; Klionsky, D.J. Potential therapeutic applications of autophagy. Nat. Rev. Drug Discov., 2007, 6(4), 304-312.
39. Rubinsztein, C.D. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature, 2006, 443(7113), 780-786.
40. Eskelinen, E.L. Maturation of autophagic vacuoles in Mammalian cells. Autophagy, 2005, 1(1), 1-10.
41. Cuervo, A.M. Autophagy and aging: keeping that old broom working. Trends Genet., 2008, 24(12), 604-612.
42. Ahlberg, J.; Marzella, L.; Glaumann, H. Uptake and degradation of proteins by isolated rat liver lysosomes. Suggestion of a microautophagic pathway of proteolysis. Lab. Invest., 1982, 47(6), 523-532.
43. Cuervo, A.M; Dice, J.F. Age related decline in chaperone-mediated autophagy. J. Biol. Chem., 2000, 275(40), 31505-31513.
44. Glaumann, H. Crinophagy as a means for degradatine excess secretory proteins in rat liver. Revis. Biol. Cellular. 1989, 20, 97-110.
45. Seglen, P.O.; Gordon, P.B. 3-Methyladenine. Specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc. Natl. Acad. Sci. USA, 1982, 79(6), 1889-1892.
46. Petiot, A.; Ogier-Denis, E.; Blommaart, E.F.; Meijer, A.J.; Codogno, P. Distinct classes of phosphatidylinositol 30-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J. Biol. Chem., 2000, 275(2), 992-998.
47. Tassa, A.; Roux, M.P.; Attaix, D.; Bechet, D.M. Class III phosphoinositide 3-kinase-beclin1 complex mediates the amino acid-dependent regulation of autophagy in C2C12 myotubes. Biochem. J., 2003, 376, 577-586.
48. Eskelinen, E.L.; Prescott, A.R.; Cooper, J.; Brachmann, S.M.; Wang, L.; Tang, X.; Backer, J.M.; Lucocq, J.M. Inhibition of autophagy in mitotic animal cells. Traffic, 2002, 3(12), 878-893.
49. Lum, J.J.; DeBerardinis, R.J.; Thompson, C.B. Autophagy in metazoans: cell survival in the land of plenty. Nat. Rev. Mol. Cell Biol., 2005, 6(6), 439-448.
50. Ylä-Anttila, P.; Vihinen, H.; Jokitalo, E.; Eskelinen, E.L. Monitoring autophagy by electron microscopy in mammalian cells. Methods Enzymol., 2009, 452, 143-164.
51. Eskelinen, E.L. New insights into the mechanisms of macroautophagy in mammalian cells. Int. Rev. Cell Mol. Biol., 2008, 266, 207-247.
52. Xie, Z.; Klonsky, D.J. Autophagosome formation: core machinery and adaptations. Nat. Cell. Biol., 2009, 9(10), 1102-1109.
53. Fengrud, M.; Erichsen, E.S.; Berg, T.O.; Raiborg, C.; Seglen, P.O. Ultrastructure characterization of the limiting membranes of isolatated autophagosomes and amphisomes by freeze-fracture eletron-microscopy. Eur. J. Cell Biol., 2000, 79(12), 871-882.
54. Berg, T.O.; Fengsrud, M.; Stromhaug, P.E.; Berg, T.; Seglen, P.O. Isolation and characterization of rat liver amphisomes: evidence for fusion of autophagosomes with both early and late endosomes. J. Biol. Chem., 1998, 273(34), 21883-21892.
55. Eskelinen, E.L. Roles of LAMP-1 and LAMP-2 in lysosome biogenesis and autophagy. Mol. Aspects Med., 2006, 27(5-6), 495-502.
56. Felbor, U.; Kessler, B.; Mothes, W.; Goebel, H.H.; Ploegh, H.L.; Bronson, R.T.; Olsen, B.R. Neuronal loss and brain atrophy in mice lacking cathepsins B and L. Proc. Natl. Acad. Sci. USA, 2002, 99(12), 7883-7888.
57. Koike, M.; Nakanishi, H.; Saftig, P.; Ezaki, J.; Isahara, K.; Ohsawa, Y.; Schulz-Schaeffer, W.; Watanabe, T.; Waguri, S.; Kametaka, S.; Shibata, M.; Yamamoto, K.; Kominami, E.; Peters, C.; von Figura, K.; Uchiyama, Y. Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons. J. Neurosci., 2000, 20(18), 6898-6906.
58. Fass, E.; Shvets, E.; Degani, I.; Hirschberg, K.; Elazar, Z. Microtubulessupportproductionofstarvation-induced autophagosomes but not their targeting and fusion with lysosomes. J. Biol. Chem., 2006, 281(47), 36303-36316.
59. Jahreiss, L.; Menzies, F.M.; Rubinsztein, D.C. The itinerary of autophagosomes: from peripheral formation to kiss-and-run fusion with lysosomes. Traffic, 2008, 9(4), 574-587.
60. Ravikumar, B.; Acevedo-Arozena, A.; Imarisio, S.; Berger, Z.; Vacher, C.; O'Kane, C.J.; Brown, S.D.; Rubinsztein, D.C. Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nat. Genet., 2005, 37, 771-776.
61. Rink, J.; Ghigo, E.; Kalaidzidis, Y.; Zerial, M. Rab conversion as a mechanism of progression from early to late endosomes. Cell, 2005, 122(5), 735-749.
62. Lai, C.; Xie, C.; Shim, H.; Chandran, J.; Howell, B.W.; Cai, H. Regulation of endosomal motility and degradation by amyotrophic lateral sclerosis 2/alsin. Mol. Brain, 2009, 2, 23.
63. Nickerson, D.P.; Russell, M.R.; Odorizzi, G. A concentric circle model of multivesicular body cargo sorting. EMBO Rep., 2007, 8(7), 644-650.
64. Lee, J.A.; Beigneux, A.; Ahmad, S.T.; Young, S.G.; Gao, F.B. ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration. Curr. Biol., 2007, 17, 1561-1567.
65. Filimonenko, M.; Stuffers, S.; Raiborg, C.; Yamamoto, A.; Malerod, L.; Fisher, E.M.; Isaacs, A.; Brech, A.; Stenmark, H.; Simonsen, A. Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J. Cell. Biol., 2007, 179, 485-500.
66. Hetz, C.; Thielen, P.; Matus, S.; Nassif, M.; Court, F.; Kiffin, R.; Martinez, G.; Cuervo, A.M.; Brown, R.H.; Glimcher, L.H. XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev., 2009, 23(19), 2294-2306.
67. Kabuta, T.; Suzuki, Y.; Wada, K. Degradation of amyotrophic lateral sclerosis-linked mutant Cu, Zn-superoxide dismutase proteins by macroautophagy and the proteasome. J. Biol. Chem., 2006, 281(41), 30524-30533.
68. Morimoto, N.; Nagai M.; Ohta, Y.; Miyazaki, K.; Kurata, T.; Morimoto, M.; Murakami, T.; Takehisa, Y.; Ikeda, Y.; Kamiya, T.; Abe, K. Increased autophagy in transgenic mice with a G93A mutant SOD1 gene. Brain Res., 2007, 1167, 112-117.
69. Li, L.; Zhang, X.; Le, W. Altered macroautophagy in the spinal cord of SOD1 mutant mice. Autophagy, 2008, 4(3), 290-293.
70. Pankiv, S.; Clausen, T.H.; Lamark, T.; Brech, A.; Bruun, J.A.; Outzen, H.; Overvatn, A.; Bjorkoy, G.; Johansen, T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem., 2007, 282, 24131-24145.
71. Wooten, M.W.; Geetha, T.; Babu, J.R.; Seibenhener, M.L.; Peng, J.; Cox, N.; Diaz-Meco, M.T.; Moscat, J. Essential role of sequestosome 1/p62 in regulating accumulation of Lys63-ubiquitinated proteins. J. Biol. Chem., 2008, 283(11), 6783-6789.
72. Komatsu, M.; Waguri, S.; Koike, M.; Sou, Y.S.; Ueno, T.; Hara, T.; Mizushima, N.; Iwata, J.; Ezaki, J.; Murata, S.; Hamazaki, J.; Nishito, Y.; Iemura, S.; Natsume, T.; Yanagawa, T.; Uwayama, J.; Warabi, E.; Yoshida, H.; Ishii, T.; Kobayashi, A.; Yamamoto, M.; Yue, Z.; Uchiyama, Y.; Kominami, E.; Tanaka, K. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell, 2007, 131(6), 1149-1163.
73. Tan, J.M.; Wong, E.S.; Dawson, V.L.; Dawson, T.M.; Lim, K.L. Lysine 63-linked polyubiquitin potentially partners with p62 to promote the clearance of protein inclusions by autophagy. Autophagy, 2008, 4(2), 251-253.
74. Gal, J.; Ström, A.L.; Kilty, R.; Zhang, F.; Zhu, H. p62 accumulates and enhances aggregate formation in model systems of familial amyotrophic lateral sclerosis. J. Biol. Chem., 2007, 282(15), 11068-11077.
75. Kunita, R.; Otomo, A.; Mizumura, H.; Suzuki-Utsunomiya, K.; Hadano, S.; Ikeda, J.E. The Rab5 activator ALS2/alsin acts as a novel Rac1 effector through Rac1-activated endocytosis. J. Biol. Chem., 2007, 282(22), 16599-16611.
76. Otomo, A.; Kunita, R.; Suzuki-Utsunomiya, K.; Mizumura, H.; Onoe, K.; Osuga, H.; Hadano, S.; Ikeda, J.E. ALS2/alsin deficiency in neurons leads to mild defects in macropinocytosis and axonal growth. Biochem. Biophys. Res. Commun., 2008, 370(1), 87-92.
77. Hadano, S.; Benn, S.C.; Kakuta, S.; Otomo, A.; Sudo, K.; Kunita, R.; Suzuki-Utsunomiya, K.; Mizumura, H.; Shefner, J.M.; Cox, G.A.; Iwakura, Y.; Brown, R.H. Jr.; Ikeda, J.E. Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking. Hum. Mol. Genet., 2006, 15(2), 233-250.
78. Devon, R.S.; Orban, P.C.; Gerrow, K.; Barbieri, M.A.; Schwab, C.; Cao, L.P.; Helm, J.R.; Bissada, N.; Cruz-Aguado, R.; Davidson, T.L.; Witmer, J.; Metzler, M.; Lam, C.K.; Tetzlaff, W.; Simpson, E.M.; McCaffery, J.M.; El-Husseini, A.E; Leavitt, B.R.; Hayden, M.R. Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities. Proc. Natl. Acad. Sci. USA, 2006, 103(25), 9595-9600.
79. Lottridge, J.M.; Flannery, A.R.; Vincelli, J.L.; Stevens, T.H. Vta1p and Vps46p regulate the membrane association and ATPase activity of Vps4p at the yeast multivesicular body. Proc. Natl. Acad. Sci. USA, 2006, 103(16), 6202-6207.
80. Fader, C.M.; Colombo, M.I. Autophagy and multivesicular bodies: two closely related partners. Cell Death Differ., 2009, 16(1), 70-78.
81. Parkinson, N.; Ince, P.G.; Smith, M.O.; Highley, R.; Skibinski, G.; Andersen, P.M.; Morrison, K.E.; Pall, H.S.; Hardiman, O.; Collinge, J.; Shaw, P.J.; Fisher, E.M; MRC Proteomics in ALS Study; FReJA Consortium. ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B). Neurology, 2006, 67, 1074-1077.
82. Komatsu, M.; Waguri, S.; Chiba, T.; Murata, S.; Iwata, J.; Tanida, I.; Ueno, T.; Koike, M.; Uchiyama, Y.; Kominami, E.; Tanaka, K. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature, 2006, 441(7095), 880-884.
83. Juhasz, G.; Erdi, B.; Sass, M.; Neufeld, T.P. Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila. Genes Dev., 2007, 21, 3061-3066.
84. Simonsen, A.; Cumming, R.C.; Brech, A.; Isakson, P.; Schubert, D.R.; Finley, K.D. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy, 2008, 4, 176-184.
85. Rusten, T.E.; Filimonenko, M.; Rodahl, L.M.; Stenmark, H.; Simonsen, A. ESCRTing autophagic clearance of aggregating proteins. Autophagy, 2007, 4, 1166-1172.
86. 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 taunegative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun., 2006, 351, 602-611.
87. Neumann, M.; Sampathu, D.M.; Kwong, L.K.; Truax, A.C.; Micsenyi, M.C.; Chou, T.T.; Bruce, J.; Schuck, T.; Grossman, M.; Clark, C.M.; McCluskey, L.F.; Miller, B.L.; Masliah, E.; Mackenzie, I.R.; Feldman, H.; Feiden, W.; Kretzschmar, H.A.; Trojanowski, J.Q.; Lee, V.M. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science, 2006, 314, 130-133.
88. Ou, S.H.; Wu, F.; Harrich, D.; García-Martínez, L.F.; Gaynor, R.B. Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J. Virol., 1995, 69(6), 3584-3596.
89. Andersson, M.K.; Ståhlberg, A.; Arvidsson, Y.; Olofsson, A.; Semb, H.; Stenman, G.; Nilsson, O.; Aman P. The multifunctional FUS, EWS and TAF15 proto-oncoproteins show cell type-specific expression patterns and involvement in cell spreading and stress response. BMC Cell Biol., 2009, 11(9), 37.
90. Buratti, E.; Dörk, T.; Zuccato, E.; Pagani, F.; Romano, M.; Baralle, F.E. Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J., 2001, 20(7), 1774-1784.
91. Buratti, E.; Brindisi, A.; Giombi, M.; Tisminetzky, S.; Ayala, Y.M.; Baralle, F.E. TDP-43 binds heterogeneous nuclear ribonucleoprotein A/B through its C-terminal tail: an important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon 9 splicing. J. Biol. Chem., 2005, 280(45), 37572-37584.
92. Ayala, Y.M.; Zago, P.; D'Ambrogio, A.; Xu, Y.F.; Petrucelli, L.; Buratti, E.; Baralle, F.E. Structural determinants of the cellular localization and shuttling of TDP-43. J. Cell. Sci., 2008, 121(Pt 22), 3778-3785.
93. Buratti, E.; Baralle, F.E. Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Front. Biosci., 2008, 13, 867-878.
94. Corrado, L.; Ratti, A.; Gellera, C.; Buratti, E.; Castellotti, B.; Carlomagno, Y.; Ticozzi, N.; Mazzini, L.; Testa, L.; Taroni, F.; Baralle, F.E.; Silani, V.; D'Alfonso, S. High frequency of TARDBP gene mutations in Italian patients with amyotrophic lateral sclerosis. Hum. Mutat., 2009, 30(4), 688-694.
95. Daoud, H.; Valdmanis, P.N.; Kabashi, E.; Dion, P.; Dupré, N.; Camu, W.; Meininger, V.; Rouleau, G.A. Contribution of TARDBP mutations to sporadic amyotrophic lateral sclerosis. J. Med. Genet., 2009, 46(2), 112-114.
96. Gitcho, M.A.; Baloh, R.H.; Chakraverty, S.; Mayo, K.; Norton, J.B.; Levitch, D.; Hatanpaa, K.J.; White, C.L. 3rd, Bigio, E.H.; Caselli, R.; Baker, M.; Al-Lozi, M.T.; Morris, J.C.; Pestronk, A.; Rademakers, R.; Goate, A.M.; Cairns, N.J. TDP-43 A315T mutation in familial motor neuron disease. Ann. Neurol., 2008, 63(4), 535-538.
97. Kabashi, E.; Valdmanis, P.N.; Dion, P.; Spiegelman, D.; McConkey, B.J.; Vande Velde, C.; Bouchard, J.P.; Lacomblez, L.; Pochigaeva, K.; Salachas, F.; Pradat, P.F.; Camu, W.; Meininger, V.; Dupre, N.; Rouleau, G.A. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet., 2008, 40(5), 572-574.
98. Wang, I.F., Reddy, N.M.; Shen, C.K. Higher order arrangement of the eukaryotic nuclear bodies. Proc. Natl. Acad. Sci. USA, 2002, 99(21), 13583-13588.
99. Strong, M.J.; Volkening, K.; Hammond, R.; Yang, W.; Strong, W.; Leystra-Lantz, C.; Shoesmith, C. TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol. Cell. Neurosci., 2007, 35(2), 320-327.
100. Wang, I.F.; Wu, L.S.; Chang, H.Y.; Shen, C.K. TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor. J. Neurochem., 2008, 105(3), 797-806.
101. Mackenzie, I.R.; Feldman, H.H. Ubiquitin immunohistochemistry suggests classic motor neuron disease, motor neuron disease with dementia, and frontotemporal dementia of the motor neuron disease type represent a clinicopathologic spectrum. J. Neuropathol. Exp. Neurol., 2005, 64(8), 730-739.
102. Mackenzie, I.R.; Bigio, E.H.; Ince, P.G.; Geser, F.; Neumann, M.; Cairns, N.J.; Kwong, L.K.; Forman, M.S.; Ravits, J.; Stewart, H.; Eisen, A.; McClusky, L.; Kretzschmar, H.A.; Monoranu, C.M.; Highley, J.R.; Kirby, J.; Siddique, T.; Shaw, P.J.; Lee, V.M.; Trojanowski, J.Q. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann. Neurol., 2007, 61(5), 427-434.
103. Neumann, M. Molecular Neuropathology of TDP-43 Proteinopathies. Int. J. Mol. Sci., 2009, 10(1), 232-246.
104. Holm, I.E.; Englund, E.; Mackenzie, I.R.; Johannsen, P.; Isaacs, A.M. A reassessment of the neuropathology of frontotemporal dementia linked to chromosome 3. J. Neuropathol. Exp. Neurol., 2007, 66(10), 884-891.
105. Roeber, S.; Mackenzie, I.R.; Kretzschmar, H.A.; Neumann, M. TDP-43-negative FTLD-U is a significant new clinico-pathological subtype of FTLD. Acta Neuropathol., 2008, 116(2), 147-157.
106. Mackenzie, I.R.; Neumann, M.; Bigio, E.H.; Cairns, N.J.; Alafuzoff, I.; Kril, J.; Kovacs, G.G.; Ghetti, B., Halliday, G.; Holm, I.E.; Ince, P.G.; Kamphorst, W.; Revesz, T.; Rozemuller, A.J.; Kumar-Singh, S.; Akiyama, H.; Baborie, A.; Spina, S.; Dickson, D.W.; Trojanowski, J.Q.; Mann, D.M. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol., 2010, 119(1), 1-4.
107. Mackenzie, I.R.; Neumann, M.; Bigio, E.H.; Cairns, N.J.; Alafuzoff, I.; Kril, J.; Kovacs, G.G.; Ghetti, B., Halliday, G.; Holm, I.E.; Ince, P.G.; Kamphorst, W.; Revesz, T.; Rozemuller, A.J.; Kumar-Singh, S.; Akiyama, H.; Baborie, A.; Spina, S.; Dickson, D.W.; Trojanowski, J.Q.; Mann, D.M. Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol., 2009, 117(1), 15-18.
108. Moisse, K.; Volkening, K.; Leystra-Lantz, C.; Welch, I.; Hill, T.; Strong, M.J. Divergent patterns of cytosolic TDP-43 and neuronal progranulin expression following axotomy: implications for TDP-43 in the physiological response to neuronal injury. Brain Res., 2009, 1249, 202-211.
109. Winton, M.J.; Igaz, L.M.; Wong, M.M.; Kwong, L.K.; Trojanowski, J.Q.; Lee, V.M. 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), 13302-13309.
110. Slagsvold, T.; Pattni, K.; Malerød, L.; Stenmark, H. Endosomal and non-endosomal functions of ESCRT proteins. Trends Cell Biol., 2006, 16(6), 317-326.
111. Igaz, L.M.; Kwong, L.K.; Xu, Y.; Truax, A.C.; Uryu, K.; Neumann, M.; Clark, C.M.; Elman, L.B.; Miller, B.L.; Grossman, M.; McCluskey, L.F.; Trojanowski, J.Q.; Lee, V.M. Enrichment of C-terminal fragments in TAR DNA-binding protein-43 cytoplasmic inclusions in brain but not in spinal cord of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Am. J. Pathol., 2008, 173(1), 182-194.
112. Igaz, L.M.; Kwong, L.K.; Chen-Plotkin, A.; Winton, M.J.; Unger, T.L.; Xu, Y.; Neumann, M.; Trojanowski, J.Q.; Lee, V.M. Expression of TDP-43 C-terminal fragments in vitro recapitulates pathological features of TDP-43 proteinopathies. J. Biol. Chem., 2009, 284(13), 8516-8524.
113. Nonaka, T.; Arai, T.; Buratti, E.; Baralle, F.E.; Akiyama, H.; Hasegawa, M. Phosphorylated and ubiquitinated TDP-43 pathological inclusions in ALS and FTLD-U are recapitulated in SH-SY5Y cells. FEBS Lett., 2009, 583(2), 394-400.
114. Strong, M.J.; Kesavapany, S.; Pant, H.C. The pathobiology of amyotrophic lateral sclerosis: a proteinopathy? J. Neuropathol. Exp. Neurol., 2005, 64(8), 649-664.
115. Strong, M.J. The evidence for altered RNA metabolism in amyotrophic lateral sclerosis (ALS). J. Neurol. Sci., 2010, 288(1-2), 1-12.
116. Kiebler, M.A.; Bassell, G.J. Neuronal RNA granules: movers and makers. Neuron, 2006, 51(6), 685-690.
117. Lin, A.C.; Holt, C.E. Function and regulation of local axonal translation. Curr. Opin. Neurobiol., 2008, 18(1), 60-68.
118. Bergeron, C.; Beric-Maskarel, K.; Muntasser, S.; Weyer, L.; Somerville, M.J.; Percy, M.E. Neurofilament light and polyadenylated mRNA levels are decreased in amyotrophic lateral sclerosis motor neurons. J. Neuropathol. Exp. Neurol., 1994, 53(3), 221-230.
119. Wong, N.K.; He, B.P.; Strong, M.J. Characterization of neuronal intermediate filament protein expression in cervical spinal motor neurons in sporadic amyotrophic lateral sclerosis (ALS). J. Neuropathol. Exp. Neurol., 2000, 59(11), 972-982.
120. Ge, W.W.; Leystra-Lantz, C.; Wen, W.; Strong, M.J. Selective loss of trans-actinginstability determinants of neurofilament mRNA in amyotrophic lateral sclerosis spinal cord. J. Biol. Chem., 2003, 278(29), 26558-26563.
121. Strong, M.J.; Leystra-Lantz, C.; Ge, W.W. Intermediate filament steady-state mRNA levels in amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun., 2004, 316(2), 317-322.
122. Kirkcaldie, M.T.; Dickson, T.C.; King, C.E.; Grasby, D.; Riederer, B.M.; Vickers, J.C. Neurofilament triplet proteins are restricted to a subset of neurons in the rat neocortex. J. Chem. Neuroanat., 2002, 24(3), 163-171.
123. Volkening, K.; Leystra-Lantz, C.; Yang, W.; Jaffee, H.; Strong, M.J. Tar DNA binding protein of 43 kDa (TDP-43), 14-3-3 proteins and copper/zinc superoxide dismutase (SOD1) interact to modulate NFL mRNA stability. Implications for altered RNA processing in amyotrophic lateral sclerosis (ALS). Brain Res., 2009, 1305, 168-182.
124. Kwiatkowski, T.J., Jr.; Bosco, D.A.; Leclerc, A.L.; Tamrazian, E.; Vanderburg, C.R.; Russ, C.; Davis, A.; Gilchrist, J.; Kasarskis, E.J.; Munsat, T.; Valdmanis, P.; Rouleau, G.A.; Hosler, B.A.; Cortelli, P.; de Jong, P.J.; Yoshinaga, Y.; Haines, J.L.; Pericak-Vance, M.A.; Yan, J.; Ticozzi, N.; Siddique, T.; McKenna-Yasek, D.; Sapp, P.C.; Horvitz, H.R.; Landers, J.E; Brown, R.H. Jr. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science., 2009, 323(5918), 1205-1208.
125. Vance, C.; Rogelj, B.; Hortobágyi, T.; De Vos, K.J.; Nishimura, A.L.; Sreedharan, J.; Hu, X.; Smith, B.; Ruddy, D.; Wright, P.; Ganesalingam, J.; Williams, K.L.; Tripathi, V.; Al-Saraj, S.; Al-Chalabi, A.; Leigh, P.N.; Blair, I.P.; Nicholson, G.; de Belleroche, J.; Gallo, J.M.; Miller, C.C.; Shaw, C.E. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science, 2009, 323(5918), 1208-1211.
126. Chiò, A.; Restagno, G.; Brunetti, M.; Ossola, I.; Calvo, A.; Mora, G.; Sabatelli, M.; Monsurrò, M.R.; Battistini, S.; Mandrioli, J.; Salvi, F.; Spataro, R.; Schymick, J.; Traynor, B.J.; La Bella, V.; ITALSGEN Consortium. Two Italian kindreds with familial amyotrophic lateral sclerosis due to FUS mutation. Neurobiol. Aging, 2009, 30(8), 1272-1275.
127. Crozat, A.; Aman, P.; Mandahl, N.; Ron, D. Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature, 1993, 363(6430), 640-644.
128. Rabbitts, T.H.; Forster, A.; Larson, R.; Nathan, P. Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma. Nat. Genet., 1993, 4(2), 175-180.
129. Zinszner, H.; Immanuel, D.; Yin, Y.; Liang, F.X.; Ron, D. A topogenic role for the oncogenic N-terminus of TLS: nucleolar localization when transcription is inhibited. Oncogene, 1997, 14(4), 451-461.
130. Fujii, R.; Okabe, S.; Urushido, T.; Inoue, K.; Yoshimura, A.; Tachibana, T.; Nishikawa, T.; Hicks, G.G.; Takumi, T. The RNA binding protein TLS is translocated to dendritic spines by mGluR5 activation and regulates spine morphology. Curr. Biol., 2005, 15, 587-593.
131. Doi, H.; Okamura, K.; Bauer, P.O.; Furukawa, Y.; Shimizu, H.; Kurosawa, M.; Machida, Y.; Miyazaki, H.; Mitsui, K.; Kuroiwa, Y.; Nukina, N. RNA-binding protein TLS is a major nuclear aggregate-interacting protein in huntingtin exon 1 with expanded polyglutamine-expressing cells. J. Biol. Chem., 2008, 283(10), 6489-64500.
132. Doi, H.; Koyano, S.; Suzuki, Y.; Nukina, N.; Kuroiwa, Y. The RNA-binding protein FUS/TLS is a common aggregate-interacting protein in polyglutamine diseases. Neurosci. Res., 2010, 66(1), 131-133.
133. Neumann, M.; Roeber, S.; Kretzschmar, H.A.; Rademakers, R.; Baker, M.; Mackenzie, I.R. Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol., 2009, 118(5), 605-616.
134. Neumann, M.; Rademakers, R.; Roeber, S.; Baker, M.; Kretzschmar, H.A.; Mackenzie, I.R. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain, 2009, 132(Pt 11), 2922-2931.
135. Laird, F.M.; Farah, M.H.; Ackerley, S.; Hoke, A.; Maragakis, N.; Rothstein, J.D.; Griffin, J.; Price, D.L.; Martin, L.J.; Wong, P.C. Motor neuron disease occurring in a mutant dynactin mouse model is characterized by defects in vesicular trafficking. J. Neurosci., 2008, 28(9), 1997-2005.
136. Gill, S.R.; Schroer, T.A.; Szilak, I.; Steuer, E.R.; Sheetz, M.P.; Cleveland, D.W. Dynactin, a conserved, ubiquitously expressed component of an activator of vesicle motility mediated by cytoplasmic dynein. J. Cell. Biol., 1991, 115(6), 1639-1650.
137. Schroer, T.A.; Sheetz, M.P. Two activators of microtubule-based vesicle transport. J. Cell. Biol., 1991, 115(5), 1309-1318.
138. Waterman-Storer, C.M.; Karki, S.B.; Kuznetsov, S.A.; Tabb, J.S.; Weiss, D.G.; Langford, G.M.; Holzbaur, E.L. The interaction between cytoplasmic dynein and dynactin is required for fast axonal transport. Proc. Natl. Acad. Sci. USA, 1997, 94(22), 12180-2185.
139. Köchl, R.; Hu, X.W.; Chan, E.Y.; Tooze, S.A. Microtubules facilitate autophagosome formation and fusion of autophagosomes with endosomes. Traffic, 2006, 7(2), 129-145.
140. Kimura, S.; Noda, T.; Yoshimori, T. Dynein-dependent movement of autophagosomes mediates efficient encounters with lysosomes. Cell. Struct. Funct., 2008, 33(1), 109-122.
141. Yamamoto, M.; Suzuki, S.O.; Himeno, M. The effects of dynein inhibition on the autophagic pathway in glioma cells. Neuropathology, 2010, 30(1), 1-6.
142. LaMonte, B.H.; Wallace, K.E.; Holloway, B.A.; Shelly, S.S.; Ascaño, J.; Tokito; Van Winkle, T.; Howland, D.S.; Holzbaur, E.L. Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration. Neuron, 2002, 34(5), 715-727.
143. Lagier-Tourenne, C.; Cleveland D.W. Rethinking ALS: the FUS about TDP-43. Cell, 2009, 136(6), 1001-1004.