Mechanisms of aging-related proteinopathies in Caenorhabditis elegans

Experimental and Molecular Medicine - Tập 48 Số 10 - Trang e263-e263
Dong‐Kyu Kim1, Tae Ho Kim1, Seung‐Jae Lee1
1Department of Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea

Tóm tắt

Từ khóa


Tài liệu tham khảo

White JG, Southgate E, Thomson JN, Brenner S . The structure of the nervous system of the nematode Caenorhabditis elegans. Philos Trans R Soc Lond B Biol Sci 1986; 314: 1–340.

Lai CH, Chou CY, Ch'ang LY, Liu CS, Lin W . Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics. Genome Res 2000; 10: 703–713.

Culetto E, Sattelle DB . A role for Caenorhabditis elegans in understanding the function and interactions of human disease genes. Hum Mol Genet 2000; 9: 869–877.

Link CD . Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans. Proc Natl Acad Sci USA 1995; 92: 9368–9372.

Link CD . C. elegans models of age-associated neurodegenerative diseases: lessons from transgenic worm models of Alzheimer's disease. Exp Gerontol 2006; 41: 1007–1013.

Dosanjh LE, Brown MK, Rao G, Link CD, Luo Y . Behavioral phenotyping of a transgenic Caenorhabditis elegans expressing neuronal amyloid-beta. J Alzheimers Dis 2010; 19: 681–690.

McColl G, Roberts BR, Gunn AP, Perez KA, Tew DJ, Masters CL et al. The Caenorhabditis elegans A beta 1-42 model of Alzheimer disease predominantly expresses A beta 3-42. J Biol Chem 2009; 284: 22697–22702.

Kraemer BC, Zhang B, Leverenz JB, Thomas JH, Trojanowski JQ, Schellenberg GD . Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy. Proc Natl Acad Sci USA 2003; 100: 9980–9985.

Lakso M, Vartiainen S, Moilanen AM, Sirvio J, Thomas JH, Nass R et al. Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans overexpressing human alpha-synuclein. J Neurochem 2003; 86: 165–172.

Kuwahara T, Koyama A, Gengyo-Ando K, Masuda M, Kowa H, Tsunoda M et al. Familial Parkinson mutant alpha-synuclein causes dopamine neuron dysfunction in transgenic Caenorhabditis elegans. J Biol Chem 2006; 281: 334–340.

Hamamichi S, Rivas RN, Knight AL, Cao S, Caldwell KA, Caldwell GA . Hypothesis-based RNAi screening identifies neuroprotective genes in a Parkinson's disease model. Proc Natl Acad Sci USA 2008; 105: 728–733.

Kim DK, Lim HS, Kawasaki L, Shim YH, Vaikath N, El-Agnaf OM et al. Anti-aging treatments slow propagation of synucleinopathy by restoring lysosomal function. Autophagy (e-pub ahead of print 2 August 2016; doi:10.1080/15548627.2016.1207014).

Faber PW, Alter JR, MacDonald ME, Hart AC . Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proc Natl Acad Sci U S A 1999; 96: 179–184.

Satyal SH, Schmidt E, Kitagawa K, Sondheimer N, Lindquist S, Kramer JM et al. Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans. Proc Natl Acad Sci USA 2000; 97: 5750–5755.

Jia K, Hart AC, Levine B . Autophagy genes protect against disease caused by polyglutamine expansion proteins in Caenorhabditis elegans. Autophagy 2007; 3: 21–25.

Oeda T, Shimohama S, Kitagawa N, Kohno R, Imura T, Shibasaki H et al. Oxidative stress causes abnormal accumulation of familial amyotrophic lateral sclerosis-related mutant SOD1 in transgenic Caenorhabditis elegans. Hum Mol Genet 2001; 10: 2013–2023.

Wang J, Farr GW, Hall DH, Li F, Furtak K, Dreier L et al. An ALS-linked mutant SOD1 produces a locomotor defect associated with aggregation and synaptic dysfunction when expressed in neurons of Caenorhabditis elegans. PLoS Genet 2009; 5: e1000350.

Gidalevitz T, Krupinski T, Garcia S, Morimoto RI . Destabilizing protein polymorphisms in the genetic background direct phenotypic expression of mutant SOD1 toxicity. PLoS Genet 2009; 5: e1000399.

Li J, Huang KX, Le WD . Establishing a novel C. elegans model to investigate the role of autophagy in amyotrophic lateral sclerosis. Acta Pharmacol Sin 2013; 34: 644–650.

Ash PE, Zhang YJ, Roberts CM, Saldi T, Hutter H, Buratti E et al. Neurotoxic effects of TDP-43 overexpression in C. elegans. Hum Mol Genet 2010; 19: 3206–3218.

Liachko NF, Guthrie CR, Kraemer BC . Phosphorylation promotes neurotoxicity in a Caenorhabditis elegans model of TDP-43 proteinopathy. J Neurosci 2010; 30: 16208–16219.

Zhang T, Mullane PC, Periz G, Wang J . TDP-43 neurotoxicity and protein aggregation modulated by heat shock factor and insulin/IGF-1 signaling. Hum Mol Genet 2011; 20: 1952–1965.

Vaccaro A, Tauffenberger A, Aggad D, Rouleau G, Drapeau P, Parker JA . Mutant TDP-43 and FUS cause age-dependent paralysis and neurodegeneration in C. elegans. PLoS ONE 2012; 7: e31321.

Vaccaro A, Tauffenberger A, Ash PE, Carlomagno Y, Petrucelli L, Parker JA . TDP-1/TDP-43 regulates stress signaling and age-dependent proteotoxicity in Caenorhabditis elegans. PLoS Genet 2012; 8: e1002806.

Therrien M, Rouleau GA, Dion PA, Parker JA . Deletion of C9ORF72 results in motor neuron degeneration and stress sensitivity in C. elegans. PLoS ONE 2013; 8: e83450.

Ikenaka K, Kawai K, Katsuno M, Huang Z, Jiang YM, Iguchi Y et al. dnc-1/dynactin 1 knockdown disrupts transport of autophagosomes and induces motor neuron degeneration. PLoS ONE 2013; 8: e54511.

Barbieri M, Bonafe M, Franceschi C, Paolisso G . Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans. Am J Physiol Endocrinol Metab 2003; 285: E1064–E1071.

Fontana L, Partridge L, Longo VD . Extending healthy life span—from yeast to humans. Science 2010; 328: 321–326.

Kenyon CJ . The genetics of ageing. Nature 2010; 464: 504–512.

Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G . daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 1997; 277: 942–946.

Morris JZ, Tissenbaum HA, Ruvkun G . A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 1996; 382: 536–539.

Lin K, Dorman JB, Rodan A, Kenyon C . daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 1997; 278: 1319–1322.

Henderson ST, Johnson TE . daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol 2001; 11: 1975–1980.

Lee RY, Hench J, Ruvkun G . Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. Curr Biol 2001; 11: 1950–1957.

Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R . C. elegans mutant that lives twice as long as wild type. Nature 1993; 366: 461–464.

Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 1997; 389: 994–999.

Hsu AL, Murphy CT, Kenyon C . Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 2003; 300: 1142–1145.

Morley JF, Morimoto RI . Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. Mol Biol Cell 2004; 15: 657–664.

Tullet JM, Hertweck M, An JH, Baker J, Hwang JY, Liu S et al. Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 2008; 132: 1025–1038.

Stout GJ, Stigter EC, Essers PB, Mulder KW, Kolkman A, Snijders DS et al. Insulin/IGF-1-mediated longevity is marked by reduced protein metabolism. Mol Syst Biol 2013; 9: 679.

Matilainen O, Arpalahti L, Rantanen V, Hautaniemi S, Holmberg CI . Insulin/IGF-1 signaling regulates proteasome activity through the deubiquitinating enzyme UBH-4. Cell Rep 2013; 3: 1980–1995.

Moll L, Ben-Gedalya T, Reuveni H, Cohen E . The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition. FASEB J 2016; 30: 1656–1669.

Cohen E, Bieschke J, Perciavalle RM, Kelly JW, Dillin A . Opposing activities protect against age-onset proteotoxicity. Science 2006; 313: 1604–1610.

Fonte V, Kipp DR, Yerg J 3rd, Merin D, Forrestal M, Wagner E et al. Suppression of in vivo beta-amyloid peptide toxicity by overexpression of the HSP-16.2 small chaperone protein. J Biol Chem 2008; 283: 784–791.

Alavez S, Vantipalli MC, Zucker DJ, Klang IM, Lithgow GJ . Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan. Nature 2011; 472: 226–229.

Florez-McClure ML, Hohsfield LA, Fonte G, Bealor MT, Link CD . Decreased insulin-receptor signaling promotes the autophagic degradation of beta-amyloid peptide in C. elegans. Autophagy 2007; 3: 569–580.

Morley JF, Brignull HR, Weyers JJ, Morimoto RI . The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc Natl Acad Sci USA 2002; 99: 10417–10422.

Boccitto M, Lamitina T, Kalb RG . Daf-2 signaling modifies mutant SOD1 toxicity in C. elegans. PLoS ONE 2012; 7: e33494.

Sohal RS, Weindruch R . Oxidative stress, caloric restriction, and aging. Science 1996; 273: 59–63.

Bishop NA, Guarente L . Genetic links between diet and lifespan: shared mechanisms from yeast to humans. Nat Rev Genet 2007; 8: 835–844.

Lakowski B, Hekimi S . The genetics of caloric restriction in Caenorhabditis elegans. Proc Natl Acad Sci USA 1998; 95: 13091–13096.

Jazwinski SM . Metabolic control and ageing. Trends Genet 2000; 16: 506–511.

Lambert AJ, Merry BJ . Use of primary cultures of rat hepatocytes for the study of ageing and caloric restriction. Exp Gerontol 2000; 35: 583–594.

Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, Kenyon C . A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet 2008; 4: e24.

Steinkraus KA, Smith ED, Davis C, Carr D, Pendergrass WR, Sutphin GL et al. Dietary restriction suppresses proteotoxicity and enhances longevity by an hsf-1-dependent mechanism in Caenorhabditis elegans. Aging Cell 2008; 7: 394–404.

Panowski SH, Wolff S, Aguilaniu H, Durieux J, Dillin A . PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans. Nature 2007; 447: 550–555.

Bishop NA, Guarente L . Two neurons mediate diet-restriction-induced longevity in C. elegans. Nature 2007; 447: 545–549.

Taylor RC . Aging and the UPR(ER). Brain Res e-pub ahead of print doi:10.1016/j.brainres.2016.04.017.

Sun N, Youle RJ, Finkel T . The mitochondrial basis of aging. Mol Cell 2016; 61: 654–666.

Stanfel MN, Shamieh LS, Kaeberlein M, Kennedy BK . The TOR pathway comes of age. Biochim Biophys Acta 2009; 1790: 1067–1074.

Kapahi P, Chen D, Rogers AN, Katewa SD, Li PW, Thomas EL et al. With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging. Cell Metab 2010; 11: 453–465.

Evans DS, Kapahi P, Hsueh WC, Kockel L . TOR signaling never gets old: aging, longevity and TORC1 activity. Ageing Res Rev 2011; 10: 225–237.

Laplante M, Sabatini DM . mTOR signaling in growth control and disease. Cell 2012; 149: 274–293.

Johnson SC, Rabinovitch PS, Kaeberlein M . mTOR is a key modulator of ageing and age-related disease. Nature 2013; 493: 338–345.

Robida-Stubbs S, Glover-Cutter K, Lamming DW, Mizunuma M, Narasimhan SD, Neumann-Haefelin E et al. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab 2012; 15: 713–724.

Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Muller F . Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 2003; 426: 620.

Pan KZ, Palter JE, Rogers AN, Olsen A, Chen D, Lithgow GJ et al. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell 2007; 6: 111–119.

Wang J, Robida-Stubbs S, Tullet JM, Rual JF, Vidal M, Blackwell TK . RNAi screening implicates a SKN-1-dependent transcriptional response in stress resistance and longevity deriving from translation inhibition. PLoS Genet 2010; 6: e1001048.

Rogers AN, Chen D, McColl G, Czerwieniec G, Felkey K, Gibson BW et al. Life span extension via eIF4G inhibition is mediated by posttranscriptional remodeling of stress response gene expression in C. elegans. Cell Metab 2011; 14: 55–66.

Hansen M, Taubert S, Crawford D, Libina N, Lee SJ, Kenyon C . Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 2007; 6: 95–110.

Syntichaki P, Troulinaki K, Tavernarakis N . eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans. Nature 2007; 445: 922–926.

Curran SP, Ruvkun G . Lifespan regulation by evolutionarily conserved genes essential for viability. PLoS Genet 2007; 3: e56.

Hars ES, Qi H, Ryazanov AG, Jin S, Cai L, Hu C et al. Autophagy regulates ageing in C. elegans. Autophagy 2007; 3: 93–95.

Toth ML, Sigmond T, Borsos E, Barna J, Erdelyi P, Takacs-Vellai K et al. Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans. Autophagy 2008; 4: 330–338.

Lapierre LR, De Magalhaes Filho CD, McQuary PR, Chu CC, Visvikis O, Chang JT et al. The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nat Commun 2013; 4: 2267.

Melendez A, Talloczy Z, Seaman M, Eskelinen EL, Hall DH, Levine B . Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 2003; 301: 1387–1391.

Sheaffer KL, Updike DL, Mango SE . The target of rapamycin pathway antagonizes pha-4/FoxA to control development and aging. Curr Biol 2008; 18: 1355–1364.

Seo K, Choi E, Lee D, Jeong DE, Jang SK, Lee SJ . Heat shock factor 1 mediates the longevity conferred by inhibition of TOR and insulin/IGF-1 signaling pathways in C. elegans. Aging Cell 2013; 12: 1073–1081.

Dillin A, Hsu AL, Arantes-Oliveira N, Lehrer-Graiwer J, Hsin H, Fraser AG et al. Rates of behavior and aging specified by mitochondrial function during development. Science 2002; 298: 2398–2401.

Tsang WY, Sayles LC, Grad LI, Pilgrim DB, Lemire BD . Mitochondrial respiratory chain deficiency in Caenorhabditis elegans results in developmental arrest and increased life span. J Biol Chem 2001; 276: 32240–32246.

Ventura N, Rea S, Henderson ST, Condo I, Johnson TE, Testi R . Reduced expression of frataxin extends the lifespan of Caenorhabditis elegans. Aging Cell 2005; 4: 109–112.

Feng J, Bussiere F, Hekimi S . Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans. Dev Cell 2001; 1: 633–644.

Yang W, Hekimi S . A mitochondrial superoxide signal triggers increased longevity in Caenorhabditis elegans. PLoS Biol 2010; 8: e1000556.

Wong A, Boutis P, Hekimi S . Mutations in the clk-1 gene of Caenorhabditis elegans affect developmental and behavioral timing. Genetics 1995; 139: 1247–1259.

Braeckman BP, Houthoofd K, De Vreese A, Vanfleteren JR . Apparent uncoupling of energy production and consumption in long-lived Clk mutants of Caenorhabditis elegans. Curr Biol 1999; 9: 493–496.

Ewbank JJ, Barnes TM, Lakowski B, Lussier M, Bussey H, Hekimi S . Structural and functional conservation of the Caenorhabditis elegans timing gene clk-1. Science 1997; 275: 980–983.

Lee SS, Lee RY, Fraser AG, Kamath RS, Ahringer J, Ruvkun G . A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet 2003; 33: 40–48.

Hansen M, Hsu AL, Dillin A, Kenyon C . New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen. PLoS Genet 2005; 1: 119–128.

Ray A, Martinez BA, Berkowitz LA, Caldwell GA, Caldwell KA . Mitochondrial dysfunction, oxidative stress, and neurodegeneration elicited by a bacterial metabolite in a C. elegans Parkinson's model. Cell Death Dis 2014; 5: e984.

Kayser EB, Morgan PG, Sedensky MM . GAS-1: a mitochondrial protein controls sensitivity to volatile anesthetics in the nematode Caenorhabditis elegans. Anesthesiology 1999; 90: 545–554.

Kondo M, Senoo-Matsuda N, Yanase S, Ishii T, Hartman PS, Ishii N . Effect of oxidative stress on translocation of DAF-16 in oxygen-sensitive mutants, mev-1 and gas-1 of Caenorhabditis elegans. Mech Ageing Dev 2005; 126: 637–641.

Chung KK, David KK . Emerging roles of nitric oxide in neurodegeneration. Nitric Oxide 2010; 22: 290–295.

Franco MC, Ye Y, Refakis CA, Feldman JL, Stokes AL, Basso M et al. Nitration of Hsp90 induces cell death. Proc Natl Acad Sci USA 2013; 110: E1102–E1111.

Schildknecht S, Gerding HR, Karreman C, Drescher M, Lashuel HA, Outeiro TF et al. Oxidative and nitrative alpha-synuclein modifications and proteostatic stress: implications for disease mechanisms and interventions in synucleinopathies. J Neurochem 2013; 125: 491–511.

Akbar M, Essa MM, Daradkeh G, Abdelmegeed MA, Choi Y, Mahmood L et al. Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress. Brain Res 2016; 1637: 34–55.

Ng LF, Gruber J, Cheah IK, Goo CK, Cheong WF, Shui G et al. The mitochondria-targeted antioxidant MitoQ extends lifespan and improves healthspan of a transgenic Caenorhabditis elegans model of Alzheimer disease. Free Radic Biol Med 2014; 71: 390–401.

Miquel E, Cassina A, Martinez-Palma L, Souza JM, Bolatto C, Rodriguez-Bottero S et al. Neuroprotective effects of the mitochondria-targeted antioxidant MitoQ in a model of inherited amyotrophic lateral sclerosis. Free Radic Biol Med 2014; 70: 204–213.

Springer W, Hoppe T, Schmidt E, Baumeister R . A Caenorhabditis elegans Parkin mutant with altered solubility couples alpha-synuclein aggregation to proteotoxic stress. Hum Mol Genet 2005; 14: 3407–3423.

Ved R, Saha S, Westlund B, Perier C, Burnam L, Sluder A et al. Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of alpha-synuclein, parkin, and DJ-1 in Caenorhabditis elegans. J Biol Chem 2005; 280: 42655–42668.

Wang H, Lim PJ, Yin C, Rieckher M, Vogel BE, Monteiro MJ . Suppression of polyglutamine-induced toxicity in cell and animal models of Huntington's disease by ubiquilin. Hum Mol Genet 2006; 15: 1025–1041.

Wang H, Lim PJ, Karbowski M, Monteiro MJ . Effects of overexpression of huntingtin proteins on mitochondrial integrity. Hum Mol Genet 2009; 18: 737–752.

Chan DC . Mitochondria: dynamic organelles in disease, aging, and development. Cell 2006; 125: 1241–1252.

Ron D, Walter P . Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007; 8: 519–529.

Walter P, Ron D . The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011; 334: 1081–1086.

Doyle KM, Kennedy D, Gorman AM, Gupta S, Healy SJ, Samali A . Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders. J Cell Mol Med 2011; 15: 2025–2039.

Sano R, Reed JC . ER stress-induced cell death mechanisms. Bioc him Biophys Acta 2013; 1833: 3460–3470.

Chen D, Thomas EL, Kapahi P . HIF-1 modulates dietary restrictionmediated lifespan extension via IRE-1 in Caenorhabditis elegans. PLoS Genet 2009; 5: e1000486.

Henis-Korenblit S, Zhang P, Hansen M, McCormick M, Lee SJ, Cary M et al. Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity. Proc Natl Acad Sci USA 2010; 107: 9730–9735.

Safra M, Ben-Hamo S, Kenyon C, Henis-Korenblit S . The ire-1 ER stress-response pathway is required for normal secretory-protein metabolism in C. elegans. J Cell Sci 2013; 126: 4136–4146.

Kieran D, Woods I, Villunger A, Strasser A, Prehn JH . Deletion of the BH3-only protein puma protects motoneurons from ER stress-induced apoptosis and delays motoneuron loss in ALS mice. Proc Natl Acad Sci USA 2007; 104: 20606–20611.

Matus S, Lopez E, Valenzuela V, Nassif M, Hetz C . Functional contribution of the transcription factor ATF4 to the pathogenesis of amyotrophic lateral sclerosis. PLoS ONE 2013; 8: e66672.

Matus S, Valenzuela V, Medinas DB, Hetz C . ER dysfunction and protein folding stress in ALS. Int J Cell Biol 2013; 2013: 674751.

Vaccaro A, Patten SA, Aggad D, Julien C, Maios C, Kabashi E et al. Pharmacological reduction of ER stress protects against TDP-43 neuronal toxicity in vivo. Neurobiol Dis 2013; 55: 64–75.

Ray A, Zhang S, Rentas C, Caldwell KA, Caldwell GA . RTCB-1 mediates neuroprotection via XBP-1 mRNA splicing in the unfolded protein response pathway. J Neurosci 2014; 34: 16076–16085.

Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004; 44: 601–607.

Ng CH, Mok SZ, Koh C, Ouyang X, Fivaz ML, Tan EK et al. Parkin protects against LRRK2 G2019S mutant-induced dopaminergic neurodegeneration in Drosophila. J Neurosci 2009; 29: 11257–11262.

Dauer W, Ho CC . The biology and pathology of the familial Parkinson's disease protein LRRK2. Mov Disord 2010; 25 (Suppl 1): S40–S43.

Samann J, Hegermann J, von Gromoff E, Eimer S, Baumeister R, Schmidt E . Caenorhabditits elegans LRK-1 and PINK-1 act antagonistically in stress response and neurite outgrowth. J Biol Chem 2009; 284: 16482–16491.

Yuan Y, Cao P, Smith MA, Kramp K, Huang Y, Hisamoto N et al. Dysregulated LRRK2 signaling in response to endoplasmic reticulum stress leads to dopaminergic neuron degeneration in C. elegans. PloS ONE 2011; 6: e22354.

Denzel MS, Storm NJ, Gutschmidt A, Baddi R, Hinze Y, Jarosch E et al. Hexosamine pathway metabolites enhance protein quality control and prolong life. Cell 2014; 156: 1167–1178.