{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T10:12:58Z","timestamp":1791886378578,"version":"4.3.4"},"reference-count":60,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2014,10,30]],"date-time":"2014-10-30T00:00:00Z","timestamp":1414627200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2014,10,30]],"date-time":"2014-10-30T00:00:00Z","timestamp":1414627200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective and progressive loss of motor neurons. Cystatin C (CysC), an endogenous cysteine protease inhibitor, is a major protein component of Bunina bodies observed in the spinal motor neurons of sporadic ALS and is decreased in the cerebrospinal fluid of ALS patients. Despite prominent deposition of CysC in ALS, the roles of CysC in the central nervous system remain unknown. Here, we identified the neuroprotective activity of CysC against ALS-linked mutant Cu\/Zn-superoxide dismutase (SOD1)-mediated toxicity. We found that exogenously added CysC protected neuronal cells including primary cultured motor neurons. Moreover, the neuroprotective property of CysC was dependent on the coordinated activation of two distinct pathways: autophagy induction through AMPK-mTOR pathway and inhibition of cathepsin B. Furthermore, exogenously added CysC was transduced into the cells and aggregated in the cytosol under oxidative stress conditions, implying a relationship between the neuroprotective activity of CysC and Bunina body formation. These data suggest CysC is an endogenous neuroprotective agent and targeting CysC in motor neurons may provide a novel therapeutic strategy for ALS.<\/jats:p>","DOI":"10.1038\/cddis.2014.459","type":"journal-article","created":{"date-parts":[[2014,10,30]],"date-time":"2014-10-30T14:14:46Z","timestamp":1414678486000},"page":"e1497-e1497","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Cystatin C protects neuronal cells against mutant copper-zinc superoxide dismutase-mediated toxicity"],"prefix":"10.1038","volume":"5","author":[{"given":"S","family":"Watanabe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Hayakawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Wakasugi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Yamanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,10,30]]},"reference":[{"key":"BFcddis2014459_CR1","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1038\/35097565","volume":"2","author":"DW Cleveland","year":"2001","unstructured":"Cleveland DW, Rothstein JD . From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci 2001; 2: 806\u2013819.","journal-title":"Nat Rev Neurosci"},{"key":"BFcddis2014459_CR2","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1016\/j.molmed.2004.06.009","volume":"10","author":"C Bendotti","year":"2004","unstructured":"Bendotti C, Carri MT . Lessons from models of SOD1-linked familial ALS. Trends Mol Med 2004; 10: 393\u2013400.","journal-title":"Trends Mol Med"},{"key":"BFcddis2014459_CR3","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1146\/annurev.neuro.27.070203.144244","volume":"27","author":"LI Bruijn","year":"2004","unstructured":"Bruijn LI, Miller TM, Cleveland DW . Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci 2004; 27: 723\u2013749.","journal-title":"Annu Rev Neurosci"},{"key":"BFcddis2014459_CR4","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1006\/nbdi.2001.0443","volume":"8","author":"M Watanabe","year":"2001","unstructured":"Watanabe M, Dykes-Hoberg M, Culotta VC, Price DL, Wong PC, Rothstein JD . Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. Neurobiol Dis 2001; 8: 933\u2013941.","journal-title":"Neurobiol Dis"},{"key":"BFcddis2014459_CR5","doi-asserted-by":"publisher","first-page":"3617","DOI":"10.1073\/pnas.0730423100","volume":"100","author":"JS Valentine","year":"2003","unstructured":"Valentine JS, Hart PJ . Misfolded CuZnSOD and amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 2003; 100: 3617\u20133622.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2014459_CR6","doi-asserted-by":"publisher","first-page":"12524","DOI":"10.1073\/pnas.0705044104","volume":"104","author":"A Gruzman","year":"2007","unstructured":"Gruzman A, Wood WL, Alpert E, Prasad MD, Miller RG, Rothstein JD et al. Common molecular signature in SOD1 for both sporadic and familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 2007; 104: 12524\u201312529.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2014459_CR7","doi-asserted-by":"publisher","first-page":"5074","DOI":"10.1073\/pnas.1115402109","volume":"109","author":"S Guareschi","year":"2012","unstructured":"Guareschi S, Cova E, Cereda C, Ceroni M, Donetti E, Bosco DA et al. An over-oxidized form of superoxide dismutase found in sporadic amyotrophic lateral sclerosis with bulbar onset shares a toxic mechanism with mutant SOD1. Proc Natl Acad Sci USA 2012; 109: 5074\u20135079.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2014459_CR8","doi-asserted-by":"crossref","first-page":"11282","DOI":"10.1016\/S0021-9258(18)67380-6","volume":"261","author":"M Abrahamson","year":"1986","unstructured":"Abrahamson M, Barrett AJ, Salvesen G, Grubb A . Isolation of six cysteine proteinase inhibitors from human urine. Their physicochemical and enzyme kinetic properties and concentrations in biological fluids. J Biol Chem 1986; 261: 11282\u201311289.","journal-title":"J Biol Chem"},{"key":"BFcddis2014459_CR9","doi-asserted-by":"publisher","first-page":"961","DOI":"10.3181\/00379727-124-31897","volume":"124","author":"GM Hochwald","year":"1967","unstructured":"Hochwald GM, Pepe AJ, Thorbecke GJ . Trace proteins in biological fluids. IV. Physicochemical properties and sites of formation of gamma-trace and beta-trace proteins. Proc Soc Exp Biol Med 1967; 124: 961\u2013966.","journal-title":"Proc Soc Exp Biol Med"},{"key":"BFcddis2014459_CR10","first-page":"541","volume":"3","author":"S Gauthier","year":"2011","unstructured":"Gauthier S, Kaur G, Mi W, Tizon B, Levy E . Protective mechanisms by cystatin C in neurodegenerative diseases. Front Biosci 2011; 3: 541\u2013554.","journal-title":"Front Biosci"},{"key":"BFcddis2014459_CR11","doi-asserted-by":"publisher","first-page":"1440","DOI":"10.1038\/ng.2007.29","volume":"39","author":"W Mi","year":"2007","unstructured":"Mi W, Pawlik M, Sastre M, Jung SS, Radvinsky DS, Klein AM et al. Cystatin C inhibits amyloid-beta deposition in Alzheimer's disease mouse models. Nat Genet 2007; 39: 1440\u20131442.","journal-title":"Nat Genet"},{"key":"BFcddis2014459_CR12","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.nbd.2004.08.012","volume":"18","author":"L Xu","year":"2005","unstructured":"Xu L, Sheng J, Tang Z, Wu X, Yu Y, Guo H et al. Cystatin C prevents degeneration of rat nigral dopaminergic neurons: in vitro and in vivo studies. Neurobiol Dis 2005; 18: 152\u2013165.","journal-title":"Neurobiol Dis"},{"key":"BFcddis2014459_CR13","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/0304-3940(93)90576-7","volume":"162","author":"K Okamoto","year":"1993","unstructured":"Okamoto K, Hirai S, Amari M, Watanabe M, Sakurai A . Bunina bodies in amyotrophic lateral sclerosis immunostained with rabbit anti-cystatin C serum. Neurosci Lett 1993; 162: 125\u2013128.","journal-title":"Neurosci Lett"},{"key":"BFcddis2014459_CR14","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.neulet.2009.01.026","volume":"452","author":"S Tsuji-Akimoto","year":"2009","unstructured":"Tsuji-Akimoto S, Yabe I, Niino M, Kikuchi S, Sasaki H . Cystatin C in cerebrospinal fluid as a biomarker of ALS. Neurosci Lett 2009; 452: 52\u201355.","journal-title":"Neurosci Lett"},{"key":"BFcddis2014459_CR15","doi-asserted-by":"publisher","first-page":"e15133","DOI":"10.1371\/journal.pone.0015133","volume":"5","author":"ME Wilson","year":"2010","unstructured":"Wilson ME, Boumaza I, Lacomis D, Bowser R . Cystatin C: a candidate biomarker for amyotrophic lateral sclerosis. PLoS One 2010; 5: e15133.","journal-title":"PLoS One"},{"key":"BFcddis2014459_CR16","doi-asserted-by":"publisher","first-page":"e9819","DOI":"10.1371\/journal.pone.0009819","volume":"5","author":"B Tizon","year":"2010","unstructured":"Tizon B, Sahoo S, Yu H, Gauthier S, Kumar AR, Mohan P et al. Induction of autophagy by cystatin C: a mechanism that protects murine primary cortical neurons and neuronal cell lines. PLoS One 2010; 5: e9819.","journal-title":"PLoS One"},{"key":"BFcddis2014459_CR17","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1046\/j.1471-4159.2003.01841.x","volume":"86","author":"DH Hyun","year":"2003","unstructured":"Hyun DH, Lee M, Halliwell B, Jenner P . Proteasomal inhibition causes the formation of protein aggregates containing a wide range of proteins, including nitrated proteins. J Neurochem 2003; 86: 363\u2013373.","journal-title":"J Neurochem"},{"key":"BFcddis2014459_CR18","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1046\/j.1471-4159.2002.01211.x","volume":"83","author":"M Urushitani","year":"2002","unstructured":"Urushitani M, Kurisu J, Tsukita K, Takahashi R . Proteasomal inhibition by misfolded mutant superoxide dismutase 1 induces selective motor neuron death in familial amyotrophic lateral sclerosis. J Neurochem 2002; 83: 1030\u20131042.","journal-title":"J Neurochem"},{"key":"BFcddis2014459_CR19","doi-asserted-by":"publisher","first-page":"3641","DOI":"10.1074\/jbc.M112.433615","volume":"288","author":"S Watanabe","year":"2013","unstructured":"Watanabe S, Kaneko K, Yamanaka K . Accelerated disease onset with stabilized familial amyotrophic lateral sclerosis (ALS)-linked mutant TDP-43 proteins. J Biol Chem 2013; 288: 3641\u20133654.","journal-title":"J Biol Chem"},{"key":"BFcddis2014459_CR20","doi-asserted-by":"publisher","first-page":"42984","DOI":"10.1074\/jbc.M112.417600","volume":"287","author":"Y Tashiro","year":"2012","unstructured":"Tashiro Y, Urushitani M, Inoue H, Koike M, Uchiyama Y, Komatsu M et al. Motor neuron-specific disruption of proteasomes, but not autophagy, replicates amyotrophic lateral sclerosis. J Biol Chem 2012; 287: 42984\u201342994.","journal-title":"J Biol Chem"},{"key":"BFcddis2014459_CR21","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.nbd.2013.07.011","volume":"59","author":"J Kim","year":"2013","unstructured":"Kim J, Kim TY, Cho KS, Kim HN, Koh JY . Autophagy activation and neuroprotection by progesterone in the G93A-SOD1 transgenic mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 2013; 59: 80\u201385.","journal-title":"Neurobiol Dis"},{"key":"BFcddis2014459_CR22","doi-asserted-by":"publisher","first-page":"15024","DOI":"10.1073\/pnas.1206362109","volume":"109","author":"IF Wang","year":"2012","unstructured":"Wang IF, Guo BS, Liu YC, Wu CC, Yang CH, Tsai KJ et al. Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc Natl Acad Sci USA 2012; 109: 15024\u201315029.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2014459_CR23","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1007\/s00401-002-0667-9","volume":"105","author":"H Kikuchi","year":"2003","unstructured":"Kikuchi H, Yamada T, Furuya H, Doh-ura K, Ohyagi Y, Iwaki T et al. Involvement of cathepsin B in the motor neuron degeneration of amyotrophic lateral sclerosis. Acta Neuropathol 2003; 105: 462\u2013468.","journal-title":"Acta Neuropathol"},{"key":"BFcddis2014459_CR24","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1016\/j.neuroscience.2006.07.048","volume":"143","author":"H Wootz","year":"2006","unstructured":"Wootz H, Weber E, Korhonen L, Lindholm D . Altered distribution and levels of cathepsinD and cystatins in amyotrophic lateral sclerosis transgenic mice: possible roles in motor neuron survival. Neuroscience 2006; 143: 419\u2013430.","journal-title":"Neuroscience"},{"key":"BFcddis2014459_CR25","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/j.bbrc.2010.07.084","volume":"399","author":"L Sun","year":"2010","unstructured":"Sun L, Wu Z, Baba M, Peters C, Uchiyama Y, Nakanishi H . Cathepsin B-dependent motor neuron death after nerve injury in the adult mouse. Biochem Biophys Res Commun 2010; 399: 391\u2013395.","journal-title":"Biochem Biophys Res Commun"},{"issue":"4 Suppl 2","key":"BFcddis2014459_CR26","doi-asserted-by":"publisher","first-page":"S63","DOI":"10.1212\/WNL.47.4_Suppl_2.63S","volume":"47","author":"A Hirano","year":"1996","unstructured":"Hirano A . Neuropathology of ALS: an overview. Neurology 1996; 47 (4 Suppl 2): S63\u2013S66.","journal-title":"Neurology"},{"key":"BFcddis2014459_CR27","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1001\/archneur.1967.00470210008002","volume":"16","author":"A Hirano","year":"1967","unstructured":"Hirano A, Kurland LT, Sayre GP . Familial amyotrophic lateral sclerosis. A subgroup characterized by posterior and spinocerebellar tract involvement and hyaline inclusions in the anterior horn cells. Arch Neurol 1967; 16: 232\u2013243.","journal-title":"Arch Neurol"},{"key":"BFcddis2014459_CR28","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1038\/ncb2152","volume":"13","author":"J Kim","year":"2011","unstructured":"Kim J, Kundu M, Viollet B, Guan KL . AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13: 132\u2013141.","journal-title":"Nat Cell Biol"},{"issue":"Pt 2","key":"BFcddis2014459_CR29","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1042\/bj3440427","volume":"344","author":"BT Nave","year":"1999","unstructured":"Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR . Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J 1999; 344 (Pt 2): 427\u2013431.","journal-title":"Biochem J"},{"key":"BFcddis2014459_CR30","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.nbd.2004.08.017","volume":"18","author":"KR Dave","year":"2005","unstructured":"Dave KR, Raval AP, Purroy J, Kirkinezos IG, Moraes CT, Bradley WG et al. Aberrant deltaPKC activation in the spinal cord of Wobbler mouse: a model of motor neuron disease. Neurobiol Dis 2005; 18: 126\u2013133.","journal-title":"Neurobiol Dis"},{"key":"BFcddis2014459_CR31","doi-asserted-by":"publisher","first-page":"480","DOI":"10.4161\/auto.4349","volume":"3","author":"B Ozpolat","year":"2007","unstructured":"Ozpolat B, Akar U, Mehta K, Lopez-Berestein G . PKC delta and tissue transglutaminase are novel inhibitors of autophagy in pancreatic cancer cells. Autophagy 2007; 3: 480\u2013483.","journal-title":"Autophagy"},{"key":"BFcddis2014459_CR32","doi-asserted-by":"publisher","first-page":"4571","DOI":"10.1111\/j.1742-4658.2008.06600.x","volume":"275","author":"U Ekstrom","year":"2008","unstructured":"Ekstrom U, Wallin H, Lorenzo J, Holmqvist B, Abrahamson M, Aviles FX . Internalization of cystatin C in human cell lines. FEBS J 2008; 275: 4571\u20134582.","journal-title":"FEBS J"},{"key":"BFcddis2014459_CR33","doi-asserted-by":"publisher","first-page":"17019","DOI":"10.1074\/jbc.M113.453449","volume":"288","author":"H Wallin","year":"2013","unstructured":"Wallin H, Abrahamson M, Ekstrom U . Cystatin C properties crucial for uptake and inhibition of intracellular target enzymes. J Biol Chem 2013; 288: 17019\u201317029.","journal-title":"J Biol Chem"},{"key":"BFcddis2014459_CR34","doi-asserted-by":"publisher","first-page":"3548","DOI":"10.1073\/pnas.1017275108","volume":"108","author":"C Munch","year":"2011","unstructured":"Munch C, O'Brien J, Bertolotti A . Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proc Natl Acad Sci USA 2011; 108: 3548\u20133553.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2014459_CR35","doi-asserted-by":"publisher","first-page":"12050","DOI":"10.1073\/pnas.211341698","volume":"98","author":"A Ros-Baro","year":"2001","unstructured":"Ros-Baro A, Lopez-Iglesias C, Peiro S, Bellido D, Palacin M, Zorzano A et al. Lipid rafts are required for GLUT4 internalization in adipose cells. Proc Natl Acad Sci USA 2001; 98: 12050\u201312055.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2014459_CR36","doi-asserted-by":"publisher","first-page":"7357","DOI":"10.1523\/JNEUROSCI.2718-10.2011","volume":"31","author":"H Kabayama","year":"2011","unstructured":"Kabayama H, Takeuchi M, Taniguchi M, Tokushige N, Kozaki S, Mizutani A et al. Syntaxin 1B suppresses macropinocytosis and semaphorin 3A-induced growth cone collapse. J Neurosci 2011; 31: 7357\u20137364.","journal-title":"J Neurosci"},{"key":"BFcddis2014459_CR37","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1016\/j.bbagen.2008.01.009","volume":"1780","author":"T Kurz","year":"2008","unstructured":"Kurz T, Terman A, Gustafsson B, Brunk UT . Lysosomes and oxidative stress in aging and apoptosis. Biochim Biophys Acta 2008; 1780: 1291\u20131303.","journal-title":"Biochim Biophys Acta"},{"key":"BFcddis2014459_CR38","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/j.pneurobio.2009.09.003","volume":"89","author":"T Yamashima","year":"2009","unstructured":"Yamashima T, Oikawa S . The role of lysosomal rupture in neuronal death. Prog Neurobiol 2009; 89: 343\u2013358.","journal-title":"Prog Neurobiol"},{"issue":"Pt 2","key":"BFcddis2014459_CR39","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1042\/bj3300833","volume":"330","author":"RW Mason","year":"1998","unstructured":"Mason RW, Sol-Church K, Abrahamson M . Amino acid substitutions in the N-terminal segment of cystatin C create selective protein inhibitors of lysosomal cysteine proteinases. Biochem J 1998; 330 (Pt 2): 833\u2013838.","journal-title":"Biochem J"},{"key":"BFcddis2014459_CR40","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1016\/S0092-8674(02)00835-8","volume":"110","author":"H Wichterle","year":"2002","unstructured":"Wichterle H, Lieberam I, Porter JA, Jessell TM . Directed differentiation of embryonic stem cells into motor neurons. Cell 2002; 110: 385\u2013397.","journal-title":"Cell"},{"key":"BFcddis2014459_CR41","doi-asserted-by":"publisher","first-page":"1717","DOI":"10.1126\/science.290.5497.1717","volume":"290","author":"DJ Klionsky","year":"2000","unstructured":"Klionsky DJ, Emr SD . Autophagy as a regulated pathway of cellular degradation. Science 2000; 290: 1717\u20131721.","journal-title":"Science"},{"key":"BFcddis2014459_CR42","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1038\/nature04723","volume":"441","author":"M Komatsu","year":"2006","unstructured":"Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006; 441: 880\u2013884.","journal-title":"Nature"},{"key":"BFcddis2014459_CR43","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1038\/nature04724","volume":"441","author":"T Hara","year":"2006","unstructured":"Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006; 441: 885\u2013889.","journal-title":"Nature"},{"key":"BFcddis2014459_CR44","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.4161\/auto.25188","volume":"9","author":"K Castillo","year":"2013","unstructured":"Castillo K, Nassif M, Valenzuela V, Rojas F, Matus S, Mercado G et al. Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy 2013; 9: 1308\u20131320.","journal-title":"Autophagy"},{"key":"BFcddis2014459_CR45","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1080\/17482960902803440","volume":"10","author":"C Pizzasegola","year":"2009","unstructured":"Pizzasegola C, Caron I, Daleno C, Ronchi A, Minoia C, Carri MT et al. Treatment with lithium carbonate does not improve disease progression in two different strains of SOD1 mutant mice. Amyotroph Lateral Scler 2009; 10: 221\u2013228.","journal-title":"Amyotroph Lateral Scler"},{"key":"BFcddis2014459_CR46","doi-asserted-by":"publisher","first-page":"412","DOI":"10.4161\/auto.7.4.14541","volume":"7","author":"X Zhang","year":"2011","unstructured":"Zhang X, Li L, Chen S, Yang D, Wang Y, Zhang X et al. Rapamycin treatment augments motor neuron degeneration in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Autophagy 2011; 7: 412\u2013425.","journal-title":"Autophagy"},{"key":"BFcddis2014459_CR47","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/1750-1326-8-31","volume":"8","author":"KA Staats","year":"2013","unstructured":"Staats KA, Hernandez S, Schonefeldt S, Bento-Abreu A, Dooley J, Van Damme P et al. Rapamycin increases survival in ALS mice lacking mature lymphocytes. Mol Neurodegener 2013; 8: 31.","journal-title":"Mol Neurodegener"},{"key":"BFcddis2014459_CR48","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1523\/JNEUROSCI.6554-10.2012","volume":"32","author":"MA Lim","year":"2012","unstructured":"Lim MA, Selak MA, Xiang Z, Krainc D, Neve RL, Kraemer BC et al. Reduced activity of AMP-activated protein kinase protects against genetic models of motor neuron disease. J Neurosci 2012; 32: 1123\u20131141.","journal-title":"J Neurosci"},{"key":"BFcddis2014459_CR49","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.1074\/jbc.271.3.1314","volume":"271","author":"I Ekiel","year":"1996","unstructured":"Ekiel I, Abrahamson M . Folding-related dimerization of human cystatin C. J Biol Chem 1996; 271: 1314\u20131321.","journal-title":"J Biol Chem"},{"key":"BFcddis2014459_CR50","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1002\/(SICI)1097-4652(199712)173:3<423::AID-JCP15>3.0.CO;2-C","volume":"173","author":"GS Merz","year":"1997","unstructured":"Merz GS, Benedikz E, Schwenk V, Johansen TE, Vogel LK, Rushbrook JI et al. Human cystatin C forms an inactive dimer during intracellular trafficking in transfected CHO cells. J Cell Physiol 1997; 173: 423\u2013432.","journal-title":"J Cell Physiol"},{"key":"BFcddis2014459_CR51","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/S0896-6273(00)80272-X","volume":"18","author":"LI Bruijn","year":"1997","unstructured":"Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 1997; 18: 327\u2013338.","journal-title":"Neuron"},{"key":"BFcddis2014459_CR52","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1111\/j.1471-4159.2007.04534.x","volume":"102","author":"H Yamashita","year":"2007","unstructured":"Yamashita H, Kawamata J, Okawa K, Kanki R, Nakamizo T, Hatayama T et al. Heat-shock protein 105 interacts with and suppresses aggregation of mutant Cu\/Zn superoxide dismutase: clues to a possible strategy for treating ALS. J Neurochem 2007; 102: 1497\u20131505.","journal-title":"J Neurochem"},{"key":"BFcddis2014459_CR53","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/0014-5793(88)80276-X","volume":"236","author":"M Abrahamson","year":"1988","unstructured":"Abrahamson M, Dalboge H, Olafsson I, Carlsen S, Grubb A . Efficient production of native, biologically active human cystatin C by Escherichia coli. FEBS Lett 1988; 236: 14\u201318.","journal-title":"FEBS Lett"},{"key":"BFcddis2014459_CR54","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/0378-1119(89)90214-X","volume":"79","author":"H Dalboge","year":"1989","unstructured":"Dalboge H, Jensen EB, Tottrup H, Grubb A, Abrahamson M, Olafsson I et al. High-level expression of active human cystatin C in Escherichia coli. Gene 1989; 79: 325\u2013332.","journal-title":"Gene"},{"key":"BFcddis2014459_CR55","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/0022-1759(90)90029-U","volume":"132","author":"Y Aida","year":"1990","unstructured":"Aida Y, Pabst MJ . Removal of endotoxin from protein solutions by phase separation using Triton X-114. J Immunol Methods 1990; 132: 191\u2013195.","journal-title":"J Immunol Methods"},{"key":"BFcddis2014459_CR56","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/S0009-9120(97)00049-0","volume":"30","author":"S Liu","year":"1997","unstructured":"Liu S, Tobias R, McClure S, Styba G, Shi Q, Jackowski G . Removal of endotoxin from recombinant protein preparations. Clin Biochem 1997; 30: 455\u2013463.","journal-title":"Clin Biochem"},{"key":"BFcddis2014459_CR57","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/0003-2697(89)90602-7","volume":"182","author":"SC Gill","year":"1989","unstructured":"Gill SC, von Hippel PH . Calculation of protein extinction coefficients from amino acid sequence data. Anal Biochem 1989; 182: 319\u2013326.","journal-title":"Anal Biochem"},{"key":"BFcddis2014459_CR58","doi-asserted-by":"publisher","first-page":"9678","DOI":"10.1021\/bi800699v","volume":"47","author":"D Sevlever","year":"2008","unstructured":"Sevlever D, Jiang P, Yen SH . Cathepsin D is the main lysosomal enzyme involved in the degradation of alpha-synuclein and generation of its carboxy-terminally truncated species. Biochemistry 2008; 47: 9678\u20139687.","journal-title":"Biochemistry"},{"key":"BFcddis2014459_CR59","doi-asserted-by":"publisher","first-page":"1891","DOI":"10.2353\/ajpath.2009.080680","volume":"174","author":"J Wei","year":"2009","unstructured":"Wei J, Fujita M, Nakai M, Waragai M, Sekigawa A, Sugama S et al. Protective role of endogenous gangliosides for lysosomal pathology in a cellular model of synucleinopathies. Am J Pathol 2009; 174: 1891\u20131909.","journal-title":"Am J Pathol"},{"key":"BFcddis2014459_CR60","doi-asserted-by":"publisher","first-page":"28087","DOI":"10.1074\/jbc.M704465200","volume":"282","author":"J Niwa","year":"2007","unstructured":"Niwa J, Yamada S, Ishigaki S, Sone J, Takahashi M, Katsuno M et al. Disulfide bond mediates aggregation, toxicity, and ubiquitylation of familial amyotrophic lateral sclerosis-linked mutant SOD1. J Biol Chem 2007; 282: 28087\u201328095.","journal-title":"J Biol Chem"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/cddis2014459.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2014459","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2014459.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T23:20:23Z","timestamp":1672960823000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/cddis2014459"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,10,30]]},"references-count":60,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2014,10]]}},"alternative-id":["BFcddis2014459"],"URL":"https:\/\/doi.org\/10.1038\/cddis.2014.459","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,10,30]]},"assertion":[{"value":"27 March 2014","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 July 2014","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 August 2014","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 October 2014","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}