- Ph.D., Cell and Molecular Biology, University of Tennessee, 1993
- Postdoctoral research: Columbia University
The Caldwell Laboratory, shared by co-investigators, Drs. Guy and Kim Caldwell, is focused on studying malfunction in basic cellular mechanisms associated with diseases of the nervous system. Our laboratory utilizes the microscopic nematode roundworm, C. elegans, as a model system for discovering gene function, as well as therapeutic target development for these disorders. C. elegans affords many advantages in such research as it is amenable to genetic, genomic, proteomic, and drug screening strategies and is an animal with a completely defined cell lineage, completed genome sequence, and lifespan of approximately 2-3 weeks. As opposed to the human brain, where it is estimated we have over 100 billion nerve cells, this anatomically transparent and microscopic worm contains precisely 302 neurons for which a defined neuronal connectivity map has been determined. In this regard, C. elegans is ideal for investigation of diseases associated with neuronal dysfunction and ageing. The utility of this organism for both basic and biomedical research has been well established and recognized by the fact that this animal was a subject of the 2002, 2006, and 2008 Nobel Prizes.
The Caldwell Lab has pioneered the application of C. elegans for the study of several disorders including dystonia, Parkinson’s disease, epilepsy. Other diseases under investigation in our lab include Alzheimer’s disease, ALS, and cystic fibrosis. Our research efforts aimed at gene and drug discovery to advance therapeutic development for these disorders also include application of mammalian cell culture models for target validation, as well as molecular biology and biochemical strategies for mechanistic analysis.
Support for research in the Caldwell lab comes from numerous of medical foundations, the National Institute of Health, National Science Foundation, Howard Hughes Medical Institute, and the biotechnology industry.
Ray A, Zhang, S, Rentas, C Caldwell, KA, and Caldwell, GA. 2015. RTCB-1 mediates neuroprotection via XBP-1 mRNA Splicing in the UPR pathway. J. Neurosci., 34:16076 –16085.
Ray, A, Rentas, C, Caldwell, GA, and Caldwell, KA. 2015. Phenazines cause proteotoxicity and stress in C. elegans. Neurosci Lett., 584:23-27.
Johnson, WM, Yao, C, Siedlak, S, Wang, W, Zhu, X, Caldwell, GA, Wilson-Delfosse, AL, Mieyal, JJ, and Chen, S. 2014. Glutaredoxin deficiency exacerbates neurodegeneration in C. elegans models of Parkinson’s disease. Hum. Mol. Genet., [Epub ahead of print].
Wang S, Zhang, S, Liou, L-C, Ren, Q, Zhang, Z, Caldwell, GA, Caldwell, KA, and Witt, SN. 2014. Phosphatidylethanolamine deficiency enhances α-synuclein toxicity in yeast and worm models of Parkinson’s disease. Proc. Natl. Acad. Sci. USA, 111:E3976–E3985.
Caraveo, G, Auluck, PK, Whitesell, L, Chung, C-Y, Baru, V, Mosharov, E, Yan, X, Ben Johny, M, Soste, M, Picotti, P, Kim, H, Caldwell, KA, Caldwell, GA, Sulzer, DA, Yue, DT, Lindquist, S. 2014. Calcineurin determines toxic versus beneficial responses to α-synuclein. Proc. Natl. Acad. Sci. USA, 111:E3544-52.
Knight, AL, Yan, X, Hamamichi, S, Ajjuri, RR, Mazzulli, JR, Zhang, MW, Daigle, JG, Zhang, S, Borom, AR, Roberts, LR, Lee, SK, DeLeon, SM, Viollet-Djelassi, C., Krainc, D., O’Donnell, J.M., Caldwell, K.A., and Caldwell, GA. 2014. The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson’s models. Cell Metabolism 20:145-157.
Matlack, KE, Tardiff, DF, Narayan, P, Hamamichi, S, Caldwell, KA, Caldwell, GA, and Lindquist, S. 2014. Clioquinol promotes the degradation of metal-dependent amyloid-β (Aβ) oligomers to restore endocytosis and ameliorate Aβ toxicity. Proc. Natl. Acad. Sci. USA 111:4013-4018.
Bornhorst, J, Chakraborty, S, Meyer, S, Lohren, H, Große Brinkhaus, S, Knight, AL, Caldwell, KA, Caldwell, GA, Karst, U, Schwerdtle, T, Bowman, A, and Aschner M. 2014. The effects of pdr1, djr1.1 and pink1 loss in manganese-induced toxicity and the role of α-synuclein in C. elegans. Metallomics 6:476-490.
Thompson, ML, Chen, P, Borom, AR, Roberts, NB, Caldwell, KA, and Caldwell, GA. 2014. TorsinA rescues ER-associated stress and locomotive defects in C. elegans models of ALS. Dis. Model. Mech., 7:233-243.
Munoz-Lobato F, Rodríguez-Palero MJ, Naranjo-Galindo FJ, Shephard F, Szewczyk NJ, Caldwell KA, Caldwell GA, Link CD, Miranda-Vizuete A. 2014. Protective role of DNJ-27, the worm orthologue of human ERdj5, in C. elegans models of neurodegenerative diseases. Antioxidants Redox Signaling, 2014 20:217-35.
Ray, A, Martinez, BA, Berkowitz, LA, Caldwell, GA, Caldwell, KA. 2014. Mitochondrial dysfunction, oxidative stress, and neurodegeneration elicited by a bacterial metabolite in a C. elegans Parkinson’s model. Cell Death Disease, 5:e984.
Jackrel, ME, DeSantis, ME, Martinez, BA, Castellano, LM, Stewart, RM, Caldwell, KA, Caldwell, GA, Shorter, J. 2014. Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. Cell 156:170-182.
Tardiff, DF, Jui, NT, Khurana, V, Tambe, MA, Thompson, ML, Chung, CY, Kamadurai HB, Kim HT, Lancaster, AK, Caldwell, KA, Caldwell, GA, Rochet J-C, Buchwald, SL, Lindquist, S. 2013. Yeast Reveal a “Druggable” Rsp5/Nedd4 Network that Ameliorates a-Synuclein Toxicity in Neurons. Science 342:979-83.
Dehay B, Martinez-Vicente M, Caldwell GA, Caldwell KA, Yue Z, Cookson MR, Klein C, Vila M, Bezard E (2013) Lysosomal impairment in Parkinson’s disease. Movement Disorders. 28:725-732.
Kautu, BB, Carrasquilla A, Hicks ML, Caldwell KA, Caldwell GA. 2013. Valproic acid ameliorates C. elegans dopaminergic neurodegeneration via ERK-MAPK. Neuroscience Letters 541:116-119.
Usenovic M, Knight AL, Ray A, Wong V, Brown KR, Caldwell GA, Caldwell KA, Stagljar I, Krainc D. 2012. Identification of novel ATP13A2 interactors and their role in α-synuclein misfolding and toxicity. Human Molecular Genetics 21:3785-3794.
Dexter PM, Caldwell KA, Caldwell GA. 2012. A predictable worm: Application of C. elegans for mechanistic investigation of movement disorders. Neurotherapeutics 9:393-404.
Tardiff DA, Tucci ML, Caldwell KA, Caldwell GA, Lindquist S. 2012. Different 8-hydroxyquinolines protect models of TDP-43, alpha-synuclein, and polyglutamine proteotoxicity through distinct mechanisms. Journal of Biological Chemistry 287:4107-4120.
Harrington AJ, Yacoubian TA, Slone SR, Caldwell KA, Caldwell GA. 2012. Functional analysis of VPS41-mediated neuroprotection in Caenorhabditis elegans and mammalian models of Parkinson’s disease. The Journal of Neuroscience 32:2142-2153.
Treusch S, Hamamichi S, Goodman JL, Matlack K, Chung CY, Baru V, Shulman JM, Parrado A, Bevis BJ, Valastyan JS, Han H, Lindhagen-Persson M, Reiman EM, Evans DA, Bennett DA, Olofsson A, DeJager PL, Tanzi RE, Caldwell KA, Caldwell GA, Lindquist S. 2011. Functional links between Ab toxicity, endocytic trafficking, and Alzheimer’s disease risk factors in yeast. Science 334:1241-1245.
Liu Z, Hamamichi S, Lee BD, Yang D, Ray A, Caldwell GA, Caldwell KA, Dawson TM, Smith WW, Dawson VL. 2011. Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in C. elegans and Drosophila Parkinson’s disease models. Human Molecular Genetics 20:3933-3942.
Mazzulli, JR, Xu Y-H, Sun Y, Knight AL, McLean PJ, Caldwell GA, Grabowski GA, Krainc D 2011. Gaucher’s disease glucocerebrosidase and a-synuclein form a bidirection apathogenic loop in synucleinopathies. Cell, 146:37-52.
Nery FC, Armata IA, Farley JE, Cho JA, Yaqub U, Chen P, da Hora CC, Wang Q, Tagaya M, Klein C, Tannous B, Caldwell KA, Caldwell GA, Lencer WI, Ye Y, Breakefield XO. 2011. TorsinA participates in endoplasmic reticulum-associated degradation (ERAD). Nature Communications 2:393. doi: 10.1038/ncomms1383.
Harrington AJ, Knight AL, Caldwell, GA, Caldwell KA. 2011. C. elegans as a model system for identifying effectors of α-synuclein misfolding and dopaminergic cell death associated with Parkinson’s disease. Methods 53:220-225.
Chen P, Burdette AJ, Porter CJ, Ricketts JC, Fox SA, Hewett JW, Nery FC, Berkowitz LA, Breakefield XO, Caldwell KA, Caldwell GA. 2010. The early-onset torsion dystonia associated protein, torsionA, is a homeostatic regulator of endoplasmic reticulum stress. Human Molecular Genetics 19:3502-3515.
Pivtoraiko VN, Harrington AJ, Luker AM, Caldwell GA, Caldwell KA, Roth KA, Shacka JJ. 2010. Bafilomycin attenuates neuronal cell death associated with autophagy-lysosome pathway dysfunction. Journal of Neurochemistry 114:1193-1204.
Caldwell GA, Caldwell KA. 2010. Disinfecting Dystonia? Drug discovery using worms identifies an antibiotic as a neuroprotective lead molecule for movement disorders. Future Neurology 5:473-476.
Cao S, Hewett JW, Yokoi F, Lu J, Buckley AC, Burdette AJ, Chen P, Nery FC, Li Y, Breakefield XO, Caldwell GA, Caldwell KA. 2010. Chemical enhancement of torsinA function in cell and animal models of torsion dystonia. Disease Models and Mechanisms 3:386-396.
Harrington AJ, Hamamichi S, Caldwell GA, Caldwell KA. 2010. C. elegans as a model organism to investigate molecular pathways involved in Parkinson’s disease. Developmental Dynamics 239:1282-1295.
Su LJ, Auluck PK, Outeiro TF, Yeger-Lotem E, Kritzer JA, Tardiff, DF, Strathearn KE, Liu F, Cao S, Hamamichi S, Hill KJ, Caldwell, KA, Bell GW, Fraenkel E, Cooper AA, Caldwell GA, McCaffery JM, Rochet J-C, Lindquist S. 2010. Compounds from an unbiased chemical screen reverse both ER to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson disease models. Disease Models and Mechanisms 3:194-208.
Burdette AJ, Churchill PF, Caldwell GA, Caldwell KA. 2010. The early-onset torsion dystonia associated protein, torsinA, displays molecular chaperone activity in vitro. Cell Stress and Chaperones 15:605-617.
Yacoubian TA, Slone SR, Hamamichi S, Harrington AJ, Caldwell KA, Caldwell GA, Standaert DG. 2010. Differential neuroprotective effects of 14-3-3 proteins in models of Parkinson’s disease. Cell Death and Disease 1, e2 doi:10.1038/cddis.2009.4
Ruan Q, Harrington AJ, Caldwell KA, Caldwell GA, Standaert DG. 2010. VPS41, a protein involved in lysosomal trafficking, is protective in Caenorhabditis elegans and mammalian cellular models of Parkinson’s disease. Neurobiology of Disease 37:330-338.
Faircloth LM, Churchill PF, Caldwell GA, Caldwell KA. 2009. The microtubule-associated protein, NUD-1, exhibits chaperone activity in vitro. Cell Stress and Chaperones 14:95-103.
Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S, Hill KJ, Caldwell KA, Caldwell GA, Cooper AA, Rochet J-C, Lindquist S. 2009. α-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nature Genetics 41:308-315.
Kritzer JA, Hamamichi S, McCaffery JM, Caldwell KA, Naumann TA, Caldwell GA, Lindquist S. 2009. Rapid selection of cyclic peptides that reduce alpha-synuclein toxicity in yeast and animal models. Nature Chemical Biology 5:655-663.
Caldwell KA, Tucci ML, Armagost J, Hodges TW, Chen J, Memon SB, Blalock JE, DeLeon SM, Findlay RH, Ruan Q, Webber PJ, Standaert DG, Olson JB, Caldwell GA. 2009. Investigating bacterial sources of toxicity as an environmental contributor to dopaminergic neurodegeneration. PLoS One 4(10):e7227.
Locke CJ, Kautu BB, Berry KP, Lee SK, Caldwell KA, Caldwell GA. 2009. Pharmacogenetic analysis reveals a postdevelopmental role for Rac GTPases in C. elegans dynein-mediated GABAergic vesicle transport. Genetics 183:1357-1372.
Caldwell GA, Caldwell KA. 2008. Traversing a wormhole to combat Parkinson’s disease. Disease Models and Mechanisms 1:32-36.
Gitler AD, Bevis BJ, Shorter J, Strathearn KE, Hamamichi S, Su J, Caldwell KA, Caldwell GA, Rochet J-C, McCaffery JM, Lindquist S. 2008. The Parkinson’s disease protein alpha-synuclein disrupts cellular Rab homeostasis. Proc Natl Acad Sci USA 105:145-150.
Hamamichi S, Rivas RN, Knight AL, Cao S, Caldwell KA, Caldwell GA. 2008. Hypothesis-based RNAi screening identifies neuroprotective genes in a Parkinson’s disease model. Proc Natl Acad Sci USA 105:728-733.
Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, Liu K, Xu K, Strathearn KE, Liu F, Cao S, Caldwell KA, Caldwell GA, Marsischky G, Kolodner RD, Labaer J, Rochet JC, Bonini NM, Lindquist S. 2006. Science. 313:324-328.