Caenorhabditis elegans as a model system for studying non-cellautonomous mechanisms in protein-misfolding diseases

DMM Disease Models and Mechanisms

Volumn 7, Issue 1, 2014, Pages 31-39

  Nussbaum Krammer, Carmen I ^a   Morimoto, Richard I ^a  

^a NORTHWESTERN UNIVERSITY   (United States)

Author keywords

Caenorhabditis elegans; Cell non autonomous proteotoxicity; Prion like spreading

Indexed keywords

4 AMINOBUTYRIC ACID; ACETYLCHOLINE; POLY Q CONTAINING PROTEIN; PRION PROTEIN; PROTEIN; UNCLASSIFIED DRUG; X BOX BINDING PROTEIN 1;

AMYOTROPHIC LATERAL SCLEROSIS; ANIMAL MODEL; AUTOPHAGY; CAENORHABDITIS ELEGANS; CELL COMMUNICATION; CYTOTOXICITY; DEGENERATIVE DISEASE; ENDOPLASMIC RETICULUM; ENDOPLASMIC RETICULUM STRESS; EXCITOTOXICITY; EXTRACELLULAR SPACE; HUNTINGTON CHOREA; LYSOSOME; MAMMAL CELL; MITOCHONDRION; MOTONEURON; MUSCLE CELL; NONHUMAN; PARKINSON DISEASE; POSTSYNAPTIC BODY WALL MUSCLE CELL; PRION DISEASE; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN DEGRADATION; PROTEIN FOLDING; PROTEIN HOMEOSTASIS; PROTEIN MISFOLDING; PROTEIN TRANSPORT; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; STRESS; UNFOLDED PROTEIN RESPONSE; VIRUS TRANSMISSION;

CAENORHABDITIS ELEGANS; CELL NON-AUTONOMOUS PROTEOTOXICITY; PRION-LIKE SPREADING;

ANIMALS; ANIMALS, GENETICALLY MODIFIED; CAENORHABDITIS ELEGANS; CAENORHABDITIS ELEGANS PROTEINS; DISEASE MODELS, ANIMAL; HUMANS; MICE; NEURODEGENERATIVE DISEASES; NEURONS; PRIONS; PROTEIN DENATURATION; PROTEIN FOLDING; PROTEINS; PROTEOSTASIS DEFICIENCIES;

EID: 84892399560     PISSN: 17548403     EISSN: 17548411     Source Type: Journal    
DOI: 10.1242/dmm.013011     Document Type: Review

References (124)

1. Åkerfelt, M., Morimoto, R. I. and Sistonen, L. (2010). Heat shock factors: integrators of cell stress, development and lifespan. Nat. Rev. Mol. Cell Biol. 11, 545-555.
2. Ananthan, J., Goldberg, A. L. and Voellmy, R. (1986). Abnormal proteins serve as eukaryotic stress signals and trigger the activation of heat shock genes. Science 232, 522-524.
3. Ash, P. E., Zhang, Y. J., Roberts, C. M., Saldi, T., Hutter, H., Buratti, E., Petrucelli, L. and Link, C. D. (2010). Neurotoxic effects of TDP-43 overexpression in C. elegans. Hum. Mol. Genet. 19, 3206-3218.
4. Beers, D. R., Henkel, J. S., Xiao, Q., Zhao, W., Wang, J., Yen, A. A., Siklos, L., McKercher, S. R. and Appel, S. H. (2006). Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 103, 16021-16026.
5. Blake, M. J., Udelsman, R., Feulner, G. J., Norton, D. D. and Holbrook, N. J. (1991). Stress-induced heat shock protein 70 expression in adrenal cortex: an adrenocorticotropic hormone-sensitive, age-dependent response. Proc. Natl. Acad. Sci. USA 88, 9873-9877.
6. Boillée, S., Yamanaka, K., Lobsiger, C. S., Copeland, N. G., Jenkins, N. A., Kassiotis, G., Kollias, G. and Cleveland, D. W. (2006). Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389-1392.
7. Boulin, T. and Hobert, O. (2012). From genes to function: the C. elegans genetic toolbox. Wiley Interdiscip. Rev. Dev. Biol. 1, 114-137.
8. Braak, H., Braak, E. and Bohl, J. (1993). Staging of Alzheimer-related cortical destruction. Eur. Neurol. 33, 403-408.
9. Braak, H., Del Tredici, K., Bratzke, H., Hamm-Clement, J., Sandmann-Keil, D. and Rub, U. (2002). Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson's disease (preclinical and clinical stages). J. Neurol. 249 Suppl. 3, III, 1-5.
10. Brenner, S. (1974). The genetics of Caenorhabditis elegans. Genetics 77, 71-94.
11. Brignull, H. R., Moore, F. E., Tang, S. J. and Morimoto, R. I. (2006). Polyglutamine proteins at the pathogenic threshold display neuron-specific aggregation in a panneuronal Caenorhabditis elegans model. J. Neurosci. 26, 7597-7606.
12. Brundin, P., Melki, R. and Kopito, R. (2010). Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat. Rev. Mol. Cell Biol. 11, 301-307.
13. Calamini, B., Silva, M. C., Madoux, F., Hutt, D. M., Khanna, S., Chalfant, M. A., Saldanha, S. A., Hodder, P., Tait, B. D., Garza, D. et al. (2011). Small-molecule proteostasis regulators for protein conformational diseases. Nat. Chem. Biol. 8, 185-196.
14. Calixto, A., Chelur, D., Topalidou, I., Chen, X. and Chalfie, M. (2010). Enhanced neuronal RNAi in C. elegans using SID-1. Nat. Methods 7, 554-559.
15. Chalfie, M., Tu, Y., Euskirchen, G., Ward, W. W. and Prasher, D. C. (1994). Green fluorescent protein as a marker for gene expression. Science 263, 802-805.
16. Cicchetti, F., Soulet, D. and Freeman, T. B. (2011). Neuronal degeneration in striatal transplants and Huntington's disease: potential mechanisms and clinical implications. Brain 134, 641-652.
17. Clavaguera, F., Bolmont, T., Crowther, R. A., Abramowski, D., Frank, S., Probst, A., Fraser, G., Stalder, A. K., Beibel, M., Staufenbiel, M. et al. (2009). Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11, 909-913.
18. Clement, A. M., Nguyen, M. D., Roberts, E. A., Garcia, M. L., Boillée, S., Rule, M., McMahon, A. P., Doucette, W., Siwek, D., Ferrante, R. J. et al. (2003). Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302, 113-117.
19. Cohen, E., Bieschke, J., Perciavalle, R. M., Kelly, J. W. and Dillin, A. (2006). Opposing activities protect against age-onset proteotoxicity. Science 313, 1604-1610.
20. Custer, S. K., Garden, G. A., Gill, N., Rueb, U., Libby, R. T., Schultz, C., Guyenet, S. J., Deller, T., Westrum, L. E., Sopher, B. L. et al. (2006). Bergmann glia expression of polyglutamine-expanded ataxin-7 produces neurodegeneration by impairing glutamate transport. Nat. Neurosci. 9, 1302-1311.
21. Danzer, K. M., Krebs, S. K., Wolff, M., Birk, G. and Hengerer, B. (2009). Seeding induced by alpha-synuclein oligomers provides evidence for spreading of alphasynuclein pathology. J. Neurochem. 111, 192-203.
22. Danzer, K. M., Kranich, L. R., Ruf, W. P., Cagsal-Getkin, O., Winslow, A. R., Zhu, L., Vanderburg, C. R. and McLean, P. J. (2012). Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol. Neurodegener. 7, 42.
23. Desplats, P., Lee, H. J., Bae, E. J., Patrick, C., Rockenstein, E., Crews, L., Spencer, B., Masliah, E. and Lee, S. J. (2009). Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc. Natl. Acad. Sci. USA 106, 13010-13015.
24. Di Giorgio, F. P., Carrasco, M. A., Siao, M. C., Maniatis, T. and Eggan, K. (2007). Non-cell autonomous effect of glia on motor neurons in an embryonic stem cellbased ALS model. Nat. Neurosci. 10, 608-614.
25. Dosanjh, L. E., Brown, M. K., Rao, G., Link, C. D. and Luo, Y. (2010). Behavioral phenotyping of a transgenic Caenorhabditis elegans expressing neuronal amyloidbeta. J. Alzheimers Dis. 19, 681-690.
26. Durieux, J., Wolff, S. and Dillin, A. (2011). The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell 144, 79-91.
27. Eisele, Y. S., Obermüller, U., Heilbronner, G., Baumann, F., Kaeser, S. A., Wolburg, H., Walker, L. C., Staufenbiel, M., Heikenwalder, M. and Jucker, M. (2010). Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science 330, 980-982.
28. Faber, P. W., Alter, J. R., MacDonald, M. E. and Hart, A. C. (1999). Polyglutaminemediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proc. Natl. Acad. Sci. USA 96, 179-184.
29. Fatouros, C., Pir, G. J., Biernat, J., Koushika, S. P., Mandelkow, E., Mandelkow, E. M., Schmidt, E. and Baumeister, R. (2012). Inhibition of tau aggregation in a novel Caenorhabditis elegans model of tauopathy mitigates proteotoxicity. Hum. Mol. Genet. 21, 3587-3603.
30. Fawcett, T. W., Sylvester, S. L., Sarge, K. D., Morimoto, R. I. and Holbrook, N. J. (1994). Effects of neurohormonal stress and aging on the activation of mammalian heat shock factor 1. J. Biol. Chem. 269, 32272-32278.
31. Ferrante, R. J., Kowall, N. W., Beal, M. F., Richardson, E. P., Jr, Bird, E. D. and Martin, J. B. (1985). Selective sparing of a class of striatal neurons in Huntington's disease. Science 230, 561-563.
32. Forno, L. S. (1996). Neuropathology of Parkinson's disease. J. Neuropathol. Exp. Neurol. 55, 259-272.
33. Frost, B., Jacks, R. L. and Diamond, M. I. (2009). Propagation of tau misfolding from the outside to the inside of a cell. J. Biol. Chem. 284, 12845-12852.
34. Garcia, S. M., Casanueva, M. O., Silva, M. C., Amaral, M. D. and Morimoto, R. I. (2007). Neuronal signaling modulates protein homeostasis in Caenorhabditis elegans post-synaptic muscle cells. Genes Dev. 21, 3006-3016.
35. Garden, G. A. and La Spada, A. R. (2008). Molecular pathogenesis and cellular pathology of spinocerebellar ataxia type 7 neurodegeneration. Cerebellum 7, 138-149.
36. Garden, G. A., Libby, R. T., Fu, Y. H., Kinoshita, Y., Huang, J., Possin, D. E., Smith, A. C., Martinez, R. A., Fine, G. C., Grote, S. K. et al. (2002). Polyglutamineexpanded ataxin-7 promotes non-cell-autonomous purkinje cell degeneration and displays proteolytic cleavage in ataxic transgenic mice. J. Neurosci. 22, 4897-4905.
37. Gardner, B. M. and Walter, P. (2011). Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response. Science 333, 1891-1894.
38. Gidalevitz, T., Ben-Zvi, A., Ho, K. H., Brignull, H. R. and Morimoto, R. I. (2006). Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science 311, 1471-1474.
39. Gidalevitz, T., Krupinski, T., Garcia, S. and Morimoto, R. I. (2009). Destabilizing protein polymorphisms in the genetic background direct phenotypic expression of mutant SOD1 toxicity. PLoS Genet. 5, e1000399.
40. Gousset, K., Schiff, E., Langevin, C., Marijanovic, Z., Caputo, A., Browman, D. T., Chenouard, N., de Chaumont, F., Martino, A., Enninga, J. et al. (2009). Prions hijack tunnelling nanotubes for intercellular spread. Nat. Cell Biol. 11, 328-336.
41. Gu, X., Li, C., Wei, W., Lo, V., Gong, S., Li, S. H., Iwasato, T., Itohara, S., Li, X. J., Mody, I. et al. (2005). Pathological cell-cell interactions elicited by a neuropathogenic form of mutant Huntingtin contribute to cortical pathogenesis in HD mice. Neuron 46, 433-444.
42. Gu, X., André, V. M., Cepeda, C., Li, S. H., Li, X. J., Levine, M. S. and Yang, X. W. (2007). Pathological cell-cell interactions are necessary for striatal pathogenesis in a conditional mouse model of Huntington's disease. Mol. Neurodegener. 2, 8.
43. Guisbert, E., Czyz, D. M., Richter, K., McMullen, P. D. and Morimoto, R. I. (2013). Identification of a tissue-selective heat shock response regulatory network. PLoS Genet. 9, e1003466.
44. Hansen, C., Angot, E., Bergström, A. L., Steiner, J. A., Pieri, L., Paul, G., Outeiro, T. F., Melki, R., Kallunki, P., Fog, K. et al. (2011). α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J. Clin. Invest. 121, 715-725.
45. Hofmann, J. P., Denner, P., Nussbaum-Krammer, C., Kuhn, P. H., Suhre, M. H., Scheibel, T., Lichtenthaler, S. F., Schätzl, H. M., Bano, D. and Vorberg, I. M. (2013). Cell-to-cell propagation of infectious cytosolic protein aggregates. Proc. Natl. Acad. Sci. USA 110, 5951-5956.
46. Hsu, A. L., Murphy, C. T. and Kenyon, C. (2003). Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300, 1142-1145.
47. Ilieva, H., Polymenidou, M. and Cleveland, D. W. (2009). Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 187, 761-772.
48. Jackson, W. S. (2014). Selective vulnerability to neurodegenerative disease: the curious case of Prion Protein. Dis. Model. Mech. 7, 21-29.
49. Jarrett, J. T. and Lansbury, P. T., Jr (1993). Seeding "one-dimensional crystallization" of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie? Cell 73, 1055-1058.
50. Kraemer, B. C., Zhang, B., Leverenz, J. B., Thomas, J. H., Trojanowski, J. Q. and Schellenberg, G. D. (2003). Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy. Proc. Natl. Acad. Sci. USA 100, 9980-9985.
51. Krammer, C., Schätzl, H. M. and Vorberg, I. (2009a). Prion-like propagation of cytosolic protein aggregates: insights from cell culture models. Prion 3, 206-212.
52. Krammer, C., Kryndushkin, D., Suhre, M. H., Kremmer, E., Hofmann, A., Pfeifer, A., Scheibel, T., Wickner, R. B., Schätzl, H. M. and Vorberg, I. (2009b). The yeast Sup35NM domain propagates as a prion in mammalian cells. Proc. Natl. Acad. Sci. USA 106, 462-467.
53. Kuwahara, T., Koyama, A., Gengyo-Ando, K., Masuda, M., Kowa, H., Tsunoda, M., Mitani, S. and Iwatsubo, T. (2006). Familial Parkinson mutant alpha-synuclein causes dopamine neuron dysfunction in transgenic Caenorhabditis elegans. J. Biol. Chem. 281, 334-340.
54. Lai, C. H., Chou, C. Y., Ch'ang, L. Y., Liu, C. S. and Lin, W. (2000). Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics. Genome Res. 10, 703-713.
55. Lakso, M., Vartiainen, S., Moilanen, A. M., Sirviö, J., Thomas, J. H., Nass, R., Blakely, R. D. and Wong, G. (2003). Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans overexpressing human alpha-synuclein. J. Neurochem. 86, 165-172.
56. Lejeune, F. X., Mesrob, L., Parmentier, F., Bicep, C., Vazquez-Manrique, R. P., Parker, J. A., Vert, J. P., Tourette, C. and Neri, C. (2012). Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons. BMC Genomics 13, 91.
57. Li, J. Y., Englund, E., Holton, J. L., Soulet, D., Hagell, P., Lees, A. J., Lashley, T., Quinn, N. P., Rehncrona, S., Björklund, A. et al. (2008). Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat. Med. 14, 501-503.
58. Lim, M. A., Selak, M. A., Xiang, Z., Krainc, D., Neve, R. L., Kraemer, B. C., Watts, J. L. and Kalb, R. G. (2012). Reduced activity of AMP-activated protein kinase protects against genetic models of motor neuron disease. J. Neurosci. 32, 1123-1141.
59. Link, C. D. (1995). Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 92, 9368-9372.
60. Lino, M. M., Schneider, C. and Caroni, P. (2002). Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease. J. Neurosci. 22, 4825-4832.
61. Lobsiger, C. S. and Cleveland, D. W. (2007). Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. Nat. Neurosci. 10, 1355-1360.
62. Lublin, A. and Link, C. (2013). Alzheimer's Disease Drug Discovery: screening using as a model for beta-amyloid peptide-induced toxicity. Drug Discov. Today. Technol. 10, e115-e119.
63. Luk, K. C., Kehm, V., Carroll, J., Zhang, B., O'Brien, P., Trojanowski, J. Q. and Lee, V. M. (2012). Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949-953.
64. Lundmark, K., Westermark, G. T., Nyström, S., Murphy, C. L., Solomon, A. and Westermark, P. (2002). Transmissibility of systemic amyloidosis by a prion-like mechanism. Proc. Natl. Acad. Sci. USA 99, 6979-6984.
65. Maman, M., Carvalhal Marques, F., Volovik, Y., Dubnikov, T., Bejerano-Sagie, M. and Cohen, E. (2013). A neuronal GPCR is critical for the induction of the heat shock response in the nematode C. elegans. J. Neurosci. 33, 6102-6111.
66. Melo, J. A. and Ruvkun, G. (2012). Inactivation of conserved C. elegans genes engages pathogen- and xenobiotic-associated defenses. Cell 149, 452-466.
67. Meyer-Luehmann, M., Coomaraswamy, J., Bolmont, T., Kaeser, S., Schaefer, C., Kilger, E., Neuenschwander, A., Abramowski, D., Frey, P., Jaton, A. L. et al. (2006). Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313, 1781-1784.
68. Morales, R., Duran-Aniotz, C., Castilla, J., Estrada, L. D. and Soto, C. (2012). De novo induction of amyloid-β deposition in vivo. Mol. Psychiatry 17, 1347-1353.
69. Morimoto, R. I. (1998). Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev. 12, 3788-3796.
70. Morley, J. F. and Morimoto, R. I. (2004). Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. Mol. Biol. Cell 15, 657-664.
71. Morley, J. F., Brignull, H. R., Weyers, J. J. and Morimoto, R. I. (2002). The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 99, 10417-10422.
72. Münch, C., O'Brien, J. and Bertolotti, A. (2011). Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proc. Natl. Acad. Sci. USA 108, 3548-3553.
73. Nargund, A. M., Pellegrino, M. W., Fiorese, C. J., Baker, B. M. and Haynes, C. M. (2012). Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 337, 587-590.
74. Nilsson, P., Loganathan, K., Sekiguchi, M., Matsuba, Y., Hui, K., Tsubuki, S., Tanaka, M., Iwata, N., Saito, T. and Saido, T. C. (2013). Abeta secretion and plaque formation depend on autophagy. Cell Rep. 5, 61-69.
75. Nollen, E. A., Garcia, S. M., van Haaften, G., Kim, S., Chavez, A., Morimoto, R. I. and Plasterk, R. H. (2004). Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation. Proc. Natl. Acad. Sci. USA 101, 6403-6408.
76. Nonaka, T., Masuda-Suzukake, M., Arai, T., Hasegawa, Y., Akatsu, H., Obi, T., Yoshida, M., Murayama, S., Mann, D. M., Akiyama, H. et al. (2013). Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep. 4, 124-134.
77. Nussbaum-Krammer, C. I., Park, K. W., Li, L., Melki, R. and Morimoto, R. I. (2013). Spreading of a prion domain from cell-to-cell by vesicular transport in Caenorhabditis elegans. PLoS Genet. 9, e1003351.
78. Park, K. W. and Li, L. (2008). Cytoplasmic expression of mouse prion protein causes severe toxicity in Caenorhabditis elegans. Biochem. Biophys. Res. Commun. 372, 697-702.
79. Parker, J. A., Connolly, J. B., Wellington, C., Hayden, M., Dausset, J. and Neri, C. (2001). Expanded polyglutamines in Caenorhabditis elegans cause axonal abnormalities and severe dysfunction of PLM mechanosensory neurons without cell death. Proc. Natl. Acad. Sci. USA 98, 13318-13323.
80. Pasquier, J., Guerrouahen, B. S., Al Thawadi, H., Ghiabi, P., Maleki, M., Abu- Kaoud, N., Jacob, A., Mirshahi, M., Galas, L., Rafii, S. et al. (2013). Preferential transfer of mitochondria from endothelial to cancer cells through tunneling nanotubes modulates chemoresistance. J. Transl. Med. 11, 94.
81. Polymenidou, M. and Cleveland, D. W. (2012). Prion-like spread of protein aggregates in neurodegeneration. J. Exp. Med. 209, 889-893.
82. Prahlad, V. and Morimoto, R. I. (2011). Neuronal circuitry regulates the response of Caenorhabditis elegans to misfolded proteins. Proc. Natl. Acad. Sci. USA 108, 14204-14209.
83. Prahlad, V., Cornelius, T. and Morimoto, R. I. (2008). Regulation of the cellular heat shock response in Caenorhabditis elegans by thermosensory neurons. Science 320, 811-814.
84. Prusiner, S. B. (1998). Prions. Proc. Natl. Acad. Sci. USA 95, 13363-13383.
85. Raeber, A. J., Race, R. E., Brandner, S., Priola, S. A., Sailer, A., Bessen, R. A., Mucke, L., Manson, J., Aguzzi, A., Oldstone, M. B. et al. (1997). Astrocytespecific expression of hamster prion protein (PrP) renders PrP knockout mice susceptible to hamster scrapie. EMBO J. 16, 6057-6065.
86. Reddy, A., Caler, E. V. and Andrews, N. W. (2001). Plasma membrane repair is mediated by Ca(2+)-regulated exocytosis of lysosomes. Cell 106, 157-169.
87. Ren, P. H., Lauckner, J. E., Kachirskaia, I., Heuser, J. E., Melki, R. and Kopito, R. R. (2009). Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat. Cell Biol. 11, 219-225.
88. Rowland, L. P. and Shneider, N. A. (2001). Amyotrophic lateral sclerosis. N. Engl. J. Med. 344, 1688-1700.
89. Sambataro, F. and Pennuto, M. (2012). Cell-autonomous and non-cell-autonomous toxicity in polyglutamine diseases. Prog. Neurobiol. 97, 152-172.
90. Satyal, S. H., Schmidt, E., Kitagawa, K., Sondheimer, N., Lindquist, S., Kramer, J. M. and Morimoto, R. I. (2000). Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 97, 5750-5755.
91. Scherzinger, E., Sittler, A., Schweiger, K., Heiser, V., Lurz, R., Hasenbank, R., Bates, G. P., Lehrach, H. and Wanker, E. E. (1999). Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington's disease pathology. Proc. Natl. Acad. Sci. USA 96, 4604-4609.
92. Shemesh, N., Shai, N. and Ben-Zvi, A. (2013). Germline stem cell arrest inhibits the collapse of somatic proteostasis early in Caenorhabditis elegans adulthood. Aging Cell 12, 814-822.
93. Shin, J. Y., Fang, Z. H., Yu, Z. X., Wang, C. E., Li, S. H. and Li, X. J. (2005). Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J. Cell Biol. 171, 1001-1012.
94. Silva, M. C., Fox, S., Beam, M., Thakkar, H., Amaral, M. D. and Morimoto, R. I. (2011). A genetic screening strategy identifies novel regulators of the proteostasis network. PLoS Genet. 7, e1002438.
95. Silva, M. C., Amaral, M. D. and Morimoto, R. I. (2013). Neuronal reprograming of protein homeostasis by calcium-dependent regulation of the heat shock response. PLoS Genet. 9, e1003711.
96. Soto, C. (2003). Unfolding the role of protein misfolding in neurodegenerative diseases. Nat. Rev. Neurosci. 4, 49-60.
97. Speare, J. O., Offerdahl, D. K., Hasenkrug, A., Carmody, A. B. and Baron, G. S. (2010). GPI anchoring facilitates propagation and spread of misfolded Sup35 aggregates in mammalian cells. EMBO J. 29, 782-794.
98. Spees, J. L., Olson, S. D., Whitney, M. J. and Prockop, D. J. (2006). Mitochondrial transfer between cells can rescue aerobic respiration. Proc. Natl. Acad. Sci. USA 103, 1283-1288.
99. Sugi, T., Nishida, Y. and Mori, I. (2011). Regulation of behavioral plasticity by systemic temperature signaling in Caenorhabditis elegans. Nat. Neurosci. 14, 984-992.
100. Sulston, J. E. (1983). Neuronal cell lineages in the nematode Caenorhabditis elegans. Cold Spring Harb. Symp. Quant. Biol. 48, 443-452.
101. Sulston, J. E., Schierenberg, E., White, J. G. and Thomson, J. N. (1983). The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev. Biol. 100, 64-119.
102. Sun, J., Singh, V., Kajino-Sakamoto, R. and Aballay, A. (2011). Neuronal GPCR controls innate immunity by regulating noncanonical unfolded protein response genes. Science 332, 729-732.
103. Sun, J., Liu, Y. and Aballay, A. (2012). Organismal regulation of XBP-1-mediated unfolded protein response during development and immune activation. EMBO Rep. 13, 855-860.
104. Taylor, R. C. and Dillin, A. (2013). XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity. Cell 153, 1435-1447.
105. Teixeira-Castro, A., Ailion, M., Jalles, A., Brignull, H. R., Vilaça, J. L., Dias, N., Rodrigues, P., Oliveira, J. F., Neves-Carvalho, A., Morimoto, R. I. et al. (2011). Neuron-specific proteotoxicity of mutant ataxin-3 in C. elegans: rescue by the DAF- 16 and HSF-1 pathways. Hum. Mol. Genet. 20, 2996-3009.
106. Ter-Avanesyan, M. D., Dagkesamanskaya, A. R., Kushnirov, V. V. and Smirnov, V. N. (1994). The SUP35 omnipotent suppressor gene is involved in the maintenance of the non-Mendelian determinant [psi+] in the yeast Saccharomyces cerevisiae. Genetics 137, 671-676.
107. Terman, A. and Brunk, U. T. (1998). Ceroid/lipofuscin formation in cultured human fibroblasts: the role of oxidative stress and lysosomal proteolysis. Mech. Ageing Dev. 104, 277-291.
108. Treusch, S., Hamamichi, S., Goodman, J. L., Matlack, K. E., Chung, C. Y., Baru, V., Shulman, J. M., Parrado, A., Bevis, B. J., Valastyan, J. S. et al. (2011). Functional links between Aβ toxicity, endocytic trafficking, and Alzheimer's disease risk factors in yeast. Science 334, 1241-1245.
109. Urano, F., Calfon, M., Yoneda, T., Yun, C., Kiraly, M., Clark, S. G. and Ron, D. (2002). A survival pathway for Caenorhabditis elegans with a blocked unfolded protein response. J. Cell Biol. 158, 639-646.
110. van Ham, T. J., Thijssen, K. L., Breitling, R., Hofstra, R. M., Plasterk, R. H. and Nollen, E. A. (2008). C. elegans model identifies genetic modifiers of alphasynuclein inclusion formation during aging. PLoS Genet. 4, e1000027.
111. van Oosten-Hawle, P., Porter, R. S. and Morimoto, R. I. (2013). Regulation of organismal proteostasis by transcellular chaperone signaling. Cell 153, 1366-1378.
112. Wang, J., Farr, G. W., Hall, D. H., Li, F., Furtak, K., Dreier, L. and Horwich, A. L. (2009). An ALS-linked mutant SOD1 produces a locomotor defect associated with aggregation and synaptic dysfunction when expressed in neurons of Caenorhabditis elegans. PLoS Genet. 5, e1000350.
113. Wang, I. F., Chang, H. Y., Hou, S. C., Liou, G. G., Way, T. D. and James Shen, C. K. (2012). The self-interaction of native TDP-43 C terminus inhibits its degradation and contributes to early proteinopathies. Nat. Commun. 3, 766.
114. White, J. G., Southgate, E., Thomson, J. N. and Brenner, S. (1986). The structure of the nervous system of the nematode Caenorhabditis elegans. Philos. Trans. R. Soc. B 314, 1-340.
115. Wickner, R. B. (1994). [URE3] as an altered URE2 protein: evidence for a prion analog in Saccharomyces cerevisiae. Science 264, 566-569.
116. Wood, S. J., Wypych, J., Steavenson, S., Louis, J. C., Citron, M. and Biere, A. L. (1999). alpha-synuclein fibrillogenesis is nucleation-dependent. Implications for the pathogenesis of Parkinson's disease. J. Biol. Chem. 274, 19509-19512.
117. Xu, X. and Kim, S. K. (2011). The early bird catches the worm: new technologies for the Caenorhabditis elegans toolkit. Nat. Rev. Genet. 12, 793-801.
118. Yamanaka, K., Boillee, S., Roberts, E. A., Garcia, M. L., McAlonis-Downes, M., Mikse, O. R., Cleveland, D. W. and Goldstein, L. S. (2008a). Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice. Proc. Natl. Acad. Sci. USA 105, 7594-7599.
119. Yamanaka, K., Chun, S. J., Boillee, S., Fujimori-Tonou, N., Yamashita, H., Gutmann, D. H., Takahashi, R., Misawa, H. and Cleveland, D. W. (2008b). Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat. Neurosci. 11, 251-253.
120. Yang, W., Dunlap, J. R., Andrews, R. B. and Wetzel, R. (2002). Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells. Hum. Mol. Genet. 11, 2905-2917.
121. Yasuda, K., Khandare, A., Burianovskyy, L., Maruyama, S., Zhang, F., Nasjletti, A. and Goligorsky, M. S. (2011). Tunneling nanotubes mediate rescue of prematurely senescent endothelial cells by endothelial progenitors: exchange of lysosomal pool. Aging (Albany, NY) 3, 597-608.
122. Yazawa, I., Giasson, B. I., Sasaki, R., Zhang, B., Joyce, S., Uryu, K., Trojanowski, J. Q. and Lee, V. M. (2005). Mouse model of multiple system atrophy alphasynuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron 45, 847-859.
123. Zhang, B., Une, Y., Fu, X., Yan, J., Ge, F., Yao, J., Sawashita, J., Mori, M., Tomozawa, H., Kametani, F. et al. (2008). Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease. Proc. Natl. Acad. Sci. USA 105, 7263-7268.
124. Zhang, P., Judy, M., Lee, S. J. and Kenyon, C. (2013). Direct and indirect gene regulation by a life-extending FOXO protein in C. elegans: roles for GATA factors and lipid gene regulators. Cell Metab. 17, 85-100.