Cellular prion protein (PrP C) plays an important role in the cellular defense against oxidative stress. However, the exact protective mechanism of PrP C is unclear. Autophagy is essential for survival, differentiation, development, and homeostasis in several organisms. Although the role that autophagy plays in neurodegenerative disease has yet to be established, it is clear that autophagy-induced cell death is observed in neurodegenerative disorders that exhibit protein aggregations. Moreover, autophagy can promote cell survival and cell death under various conditions. In this review, we describe the involvement of autophagy in prion disease and the effects of PrP C.
References
[1]
Basler, K.; Oesch, B.; Scott, M.; Westaway, D.; W？lchli, M.; Groth, D.F.; McKinley, M.P.; Prusiner, S.B.; Weissmann, C. Scrapie and cellular PrP isoforms are encoded by the same chromosomal gene. Cell 1986, 46, 417–428, doi:10.1016/0092-8674(86)90662-8.
[2]
Kretzschmar, H.A.; Prusiner, S.B.; Stowring, L.E.; DeArmond, S.J. Scrapie prion proteins are synthesized in neurons. Am. J. Pathol. 1986, 122, 1–5.
Sales, N.; Rodolfo, K.; Hassig, R.; Faucheux, B.; Di Giamberardino, L.; Moya, K.L. Cellular prion protein localization in rodent and primate brain. Eur. J. Neurosci. 1998, 10, 2464–2471, doi:10.1046/j.1460-9568.1998.00258.x.
[5]
Bolton, D.C.; McKinley, M.P.; Prusiner, S.B. Identification of a protein that purifies with the scrapie prion. Science 1982, 218, 1309–1311.
[6]
Prusiner, S.B. Prions. Proc. Natl. Acad. Sci. USA 1998, 95, 13363–13383, doi:10.1073/pnas.95.23.13363.
[7]
Aguzzi, A.; Weissmann, C. Spongiform encephalopathies: a suspicious signature. Nature 1996, 383, 666–667, doi:10.1038/383666a0.
[8]
Weissmann, C. The Ninth Datta Lecture. Molecular biology of transmissible spongiform encephalopathies. FEBS Lett. 1996, 389, 3–11, doi:10.1016/0014-5793(96)00610-2.
[9]
Klionsky, D.J.; Emr, S.D. Autophagy as a regulated pathway of cellular degradation. Science 2000, 290, 1717–1721, doi:10.1126/science.290.5497.1717.
[10]
Petersen, A.; Larsen, K.E.; Behr, G.G.; Romero, N.; Przedborski, S.; Brundin, P.; Sulzer, D. Expanded CAG repeats in exon 1 of the Huntington's disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration. Hum. Mol. Genet. 2001, 10, 1243–1254, doi:10.1093/hmg/10.12.1243.
[11]
Selimi, F.; Lohof, A.M.; Heitz, S.; Lalouette, A.; Jarvis, C.I.; Bailly, Y.; Mariani, J. Lurcher GRID2-induced death and depolarization can be dissociated in cerebellar Purkinje cells. Neuron 2003, 37, 813–819, doi:10.1016/S0896-6273(03)00093-X.
[12]
Kabeya, Y.; Mizushima, N.; Ueno, T.; Yamamoto, A.; Kirisako, T.; Noda, T.; Kominami, E.; Ohsumi, Y.; Yoshimori, T. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 2000, 19, 5720–5728, doi:10.1093/emboj/19.21.5720.
[13]
Noda, T.; Matsuura, A.; Wada, Y.; Ohsumi, Y. Novel system for monitoring autophagy in the yeast Saccharomyces cerevisiae. Biochem. Biophys. Res. Commun. 1995, 210, 126–132, doi:10.1006/bbrc.1995.1636.
[14]
Aubert, S.; Gout, E.; Bligny, R.; Marty-Mazars, D.; Barrieu, F.; Alabouvette, J.; Marty, F.; Douce, R. Ultrastructural and biochemical characterization of autophagy in higher plant cells subjected to carbon deprivation: control by the supply of mitochondria with respiratory substrates. Cell. Biol. 1996, 133, 1251–1263, doi:10.1083/jcb.133.6.1251.
[15]
Reunanen, H.; Punnonen, E.L.; Hirsim？ki, P. Studies on vinblastine-induced autophagocytosis in mouse liver. V. A cytochemical study on the origin of membranes. Histochemistry 1985, 83, 513–517, doi:10.1007/BF00492453.
[16]
Manson, J.; West, J.D.; Thomson, V.; McBride, P.; Kaufman, M.H.; Hope, J. The prion protein gene: a role in mouse embryogenesis? Development 1992, 115, 117–122.
[17]
Cuervo, A.M. Autophagy: in sickness and in health. Trends Cell. Biol. 2004, 14, 70–77, doi:10.1016/j.tcb.2003.12.002.
[18]
Shintani, T.; Klionsky, D.J. Autophagy in health and disease: a double-edged sword. Science 2004, 306, 990–995, doi:10.1126/science.1099993.
[19]
Boellaard, J.W.; Schlote, W.; Tateishi, J. Neuronal autophagy in experimental Creutzfeldt-Jakob's disease. Acta Neuropathol. 1989, 78, 410–418, doi:10.1007/BF00688178.
[20]
Boellaard, J.W.; Kao, M.; Schlote, W.; Diringer, H. Neuronal autophagy in experimental scrapie. Acta Neuropathol. 1991, 82, 225–228.
[21]
Sch？tzl, H.M.; Laszlo, L.; Holtzman, D.M.; Tatzelt, J.; DeArmond, S.J.; Weiner, R.I.; Mobley, W.C.; Prusiner, S.B. A hypothalamic neuronal cell line persistently infected with scrapie prions exhibits apoptosis. J. Virol. 1997, 71, 8821–8831.
[22]
Liberski, P.P.; Sikorska, B.; Bratosiewicz-Wasik, J.; Gajdusek, D.C.; Brown, P. Neuronal cell death in transmissible spongiform encephalopathies (prion diseases) revisited: from apoptosis to autophagy. Int. J. Biochem. Cell. Biol. 2004, 36, 2473–2490.
[23]
Sikorska, B.; Liberski, P.P.; Giraud, P.; Kopp, N.; Brown, P. Autophagy is a part of ultrastructural synaptic pathology in Creutzfeldt-Jakob disease: a brain biopsy study. Int. J. Biochem. Cell. Biol. 2004, 36, 2563–2573, doi:10.1016/j.biocel.2004.04.014.
[24]
Dron, M.; Bailly, Y.; Beringue, V.; Haeberlé, A.M.; Griffond, B.; Risold, P.Y.; Tovey, M.G.; Laude, H.; Dandoy-Dron, F. Scrg1 is induced in TSE and brain injuries, and associated with autophagy. Eur. J. Neurosci. 2005, 22, 133–146, doi:10.1111/j.1460-9568.2005.04172.x.
[25]
Aguib, Y.; Heiseke, A.; Gilch, S.; Riemer, C.; Baier, M.; Sch？tzl, H.M.; Ertmer, A. Autophagy induction by trehalose counteracts cellular prion infection. Autophagy 2009, 5, 361–369, doi:10.4161/auto.5.3.7662.
[26]
Heiseke, A.; Aguib, Y.; Riemer, C.; Baier, M.; Sch？tzl, H.M. Lithium induces clearance of protease resistant prion protein in prion-infected cells by induction of autophagy. J. Neurochem. 2009, 109, 25–34, doi:10.1111/j.1471-4159.2009.05906.x.
[27]
Cortes, C.J.; Qin, K.; Cook, J.; Solanki, A.; Mastrianni, J.A. Rapamycin delays disease onset and prevents PrP plaque deposition in a mouse model of Gerstmann-Str？ussler-Scheinker disease. J. Neurosci. 2012, 32, 12396–12405, doi:10.1523/JNEUROSCI.6189-11.2012.
[28]
Xu, Y.; Tian, C.; Wang, S.B.; Xie, W.L.; Guo, Y.; Zhang, J.; Shi, Q.; Chen, C.; Dong, X.P. Activation of the macroautophagic system in scrapie-infected experimental animals and human genetic prion diseases. Autophagy 2012, 8, 1604–1620.
[29]
Oh, J.M.; Shin, H.Y.; Park, S.J.; Kim, B.H.; Choi, J.K.; Choi, E.K.; Carp, R.I.; Kim, Y.S. The involvement of cellular prion protein in the autophagy pathway in neuronal cells. Mol. Cell. Neurosci. 2008, 39, 238–247, doi:10.1016/j.mcn.2008.07.003.
Heitz, S.; Grant, N.J.; Bailly, Y. Doppel induces autophagic stress in prion protein-deficient Purkinje cells. Autophagy 2009, 5, 422–424, doi:10.4161/auto.5.3.7882.
[32]
Heitz, S.; Grant, N.J.; Leschiera, R.; Haeberlé, A.M.; Demais, V.; Bombarde, G.; Bailly, Y. Autophagy and cell death of Purkinje cells overexpressing Doppel in Ngsk Prnp-deficient mice. Brain. Pathol. 2010, 20, 119–132, doi:10.1111/j.1750-3639.2008.00245.x.
[33]
Wong, B.S.; Liu, T.; Paisley, D.; Li, R.; Pan, T.; Chen, S.G.; Perry, G.; Petersen, R.B.; Smith, M.A.; Melton, D.W.; Gambetti, P.; Brown, D.R.; Sy, M.S. Induction of HO-1 and NOS in doppel-expressing mice devoid of PrP: implications for doppel function. Mol. Cell. Neurosci. 2001, 17, 768–775, doi:10.1006/mcne.2001.0963.
[34]
Cui, T.; Holme, A.; Sassoon, J.; Brown, D.R. Analysis of doppel protein toxicity. Mol. Cell. Neurosci. 2003, 23, 144–155, doi:10.1016/S1044-7431(03)00017-4.
[35]
Barbieri, G.; Palumbo, S.; Gabrusiewicz, K.; Azzalin, A.; Marchesi, N.; Spedito, A.; Biggiogera, M.; Sbalchiero, E.; Mazzini, G.; Miracco, C.; Pirtoli, L.; Kaminska, B.; Comincini, S. Silencing of cellular prion protein (PrPC) expression by DNA-antisense oligonucleotides induces autophagy-dependent cell death in glioma cells. Autophagy 2011, 7, 840–853, doi:10.4161/auto.7.8.15615.
[36]
Herms, J.; Tings, T.; Gall, S.; Madlung, A.; Giese, A.; Siebert, H.; Schürmann, P.; Windl, O.; Brose, N.; Kretzschmar, H. Evidence of presynapticlocation and function of the prion protein. J. Neurosci. 1999, 19, 8866–8875.
[37]
Brown, D.R.; Wong, B.S.; Hafiz, F.; Clive, C.; Haswell, S.J.; Jones, I.M. Normal prion protein has an activity like that of superoxide dismutase. Biochem. J. 1999, 344, 1–5, doi:10.1042/0264-6021:3440001.
[38]
Lee, H.G.; Park, S.J.; Choi, E.K.; Carp, R.I.; Kim, Y.S. Increased expression of prion protein is associated with changes in dopamine metabolism and MAO activity in PC12 cells. J. Mol. Neurosci. 1999, 13, 121–126, doi:10.1385/JMN:13:1-2:121.
Mouillet-Richard, S.; Ermonval, M.; Chebassier, C.; Laplanche, J.L.; Lehmann, S.; Launay, J.M.; Kellermann, O. Signal transduction through prion protein. Science 2000, 289, 1925–1928, doi:10.1126/science.289.5486.1925.
[41]
Mange, A.; Milhavet, O.; Umlauf, D.; Harris, D.; Lehmann, S. PrP-dependent cell adhesion in N2a neuroblastoma cells. FEBS. Lett. 2002, 514, 159–162, doi:10.1016/S0014-5793(02)02338-4.
[42]
Li, A.; Harris, D.A. Mammalian prion protein suppresses Bax-induced cell death in yeast. J. Biol. Chem. 2005, 280, 17430–17434, doi:10.1074/jbc.C500058200.
[43]
Bueler, H.; Fischer, M.; Lang, Y.; Bluethmann, H.; Lipp, H.P.; DeArmond, S.J.; Prusiner, S.B.; Aguet, M.; Weissmann, C. Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 1992, 356, 577–582, doi:10.1038/356577a0.
[44]
Criado, J.R.; Sa′nchez-Alavez, M.; Conti, B.; Giacchino, J.L.; Wills, D.N.; Henriksen, S.J.; Race, R.; Manson, J.C.; Chesebro, B.; Oldstone, M.B. Mice devoid of prion protein have cognitive deficits that are rescued by reconstitution of PrP in neurons. Neurobiol. Dis. 2005, 19, 255–265, doi:10.1016/j.nbd.2005.01.001.
[45]
Weissmann, C.; Flechsig, E. PrP knock-out and PrP transgenic mice in prion research. Br. Med. Bull. 2003, 66, 43–60, doi:10.1093/bmb/66.1.43.
[46]
Prestori, F.; Rossi, P.; Bearzatto, B.; Laine′, J.; Necchi, D.; Diwakar, S.; Schiffmann, S.N.; Axelrad, H.; D'Angelo, E. Altered Neuron excitability and synaptic plasticity in the cerebellar granular layer of juvenile prion protein knock-out mice with impaired motor control. J. Neurosci. 2008, 28, 7091–7103, doi:10.1523/JNEUROSCI.0409-08.2008.
[47]
Singh, A.; Kong, Q.; Luo, X.; Petersen, R.B.; Meyerson, H.; Singh, N. Prion protein (PrP) knock-out mice show altered iron metabolism: A functional role for PrP in iron uptake and transport. PLoS ONE 2009, 4, 1–14.
Brandner, S.; Isenmann, S.; Raeber, A.; Fischer, M.; Sailer, A.; Kobayashi, Y.; Marino, S.; Weissmann, C.; Aguzzi, A. Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature 1996, 379, 339–343, doi:10.1038/379339a0.
[52]
Chu, C.T.; Plowey, E.D.; Dagda, R.K.; Hickey, R.W.; Cherra, S.J.; Clark, R.S. Autophagy in neurite injury and neurodegeneration: in vitro and in vivo models. Methods. Enzymol. 2009, 453, 217–249.
[53]
Bursch, W.; Ellinger, A.; Gerner, C.; Frohwein, U.; Schulte-Hermann, R. Programmed cell death (PCD). Apoptosis, autophagic PCD, or others? Ann. N. Y. Acad. Sci. 2000, 926, 1–12.
[54]
Dong, J.; Li, A.; Yamaguchi, N.; Sakaguchi, S.; Harris, D.A. Doppel induces degeneration of cerebellar Purkinje cells independently of Bax. Am. J. Pathol. 2007, 171, 599–607, doi:10.2353/ajpath.2007.070262.
[55]
Lee, J.A. Autophagy in neurodegeneration: two sides of the same coin. BMB Rep. 2009, 42, 324–330, doi:10.5483/BMBRep.2009.42.6.324.
