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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2015

Open Access 01-12-2015 | Research article

Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression

Authors: Xi Chen, Hannah V. McCue, Shi Quan Wong, Sudhanva S. Kashyap, Brian C. Kraemer, Jeff W. Barclay, Robert D. Burgoyne, Alan Morgan

Published in: Molecular Neurodegeneration | Issue 1/2015

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Abstract

Background

Many neurodegenerative diseases are associated with protein misfolding/aggregation. Treatments mitigating the effects of such common pathological processes, rather than disease-specific symptoms, therefore have general therapeutic potential.

Results

Here we report that the anti-epileptic drug ethosuximide rescues the short lifespan and chemosensory defects exhibited by C. elegans null mutants of dnj-14, the worm orthologue of the DNAJC5 gene mutated in autosomal-dominant adult-onset neuronal ceroid lipofuscinosis. It also ameliorates the locomotion impairment and short lifespan of worms expressing a human Tau mutant that causes frontotemporal dementia. Transcriptomic analysis revealed a highly significant up-regulation of DAF-16/FOXO target genes in response to ethosuximide; and indeed RNAi knockdown of daf-16 abolished the therapeutic effect of ethosuximide in the worm dnj-14 model. Importantly, ethosuximide also increased the expression of classical FOXO target genes and reduced protein aggregation in mammalian neuronal cells.

Conclusions

We have revealed a conserved neuroprotective mechanism of action of ethosuximide from worms to mammalian neurons. Future experiments in mouse neurodegeneration models will be important to confirm the repurposing potential of this well-established anti-epileptic drug for treatment of human neurodegenerative diseases.
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Literature
1.
Narayan P, Ehsani S, Lindquist S. Combating neurodegenerative disease with chemical probes and model systems. Nat Chem Biol. 2014;10:911–20.CrossRefPubMed
2.
3.
Nass R, Miller DM, Blakely RD. C. elegans: a novel pharmacogenetic model to study Parkinson’s disease. Parkinsonism Relat Disord. 2001;7:185–91.CrossRefPubMed
4.
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 U S A. 2000;97:5750–5.PubMedCentralCrossRefPubMed
5.
van Ham TJ, Breitling R, Swertz MA, Nollen EA. Neurodegenerative diseases: lessons from genome-wide screens in small model organisms. EMBO Mol Med. 2009;1:360–70.PubMedCentralCrossRefPubMed
6.
Chen X, Burgoyne RD. Identification of common genetic modifiers of neurodegenerative diseases from an integrative analysis of diverse genetic screens in model organisms. BMC Genomics. 2012;13:71.PubMedCentralCrossRefPubMed
7.
Zhang M, Luo G, Zhou Y, Wang S, Zhong Z. Phenotypic screens targeting neurodegenerative diseases. J Biomol Screen. 2014;19:1–16.CrossRefPubMed
8.
Corbett A, Pickett J, Burns A, Corcoran J, Dunnett SB, Edison P, et al. Drug repositioning for Alzheimer’s disease. Nat Rev Drug Discov. 2012;11:833–46.CrossRefPubMed
9.
Lublin A, Link C. Alzheimer’s disease drug discovery: screening using as a model for beta-amyloid peptide-induced toxicity. Drug Discov Today Technol. 2013;10:e115–9.PubMedCentralCrossRef
10.
McCormick AV, Wheeler JM, Guthrie CR, Liachko NF, Kraemer BC. Dopamine D2 receptor antagonism suppresses tau aggregation and neurotoxicity. Biol Psychiatry. 2013;73:464–71.PubMedCentralCrossRefPubMed
11.
Sleigh JN, Buckingham SD, Esmaeili B, Viswanathan M, Cuppen E, Westlund BM, et al. A novel Caenorhabditis elegans allele, smn-1(cb131), mimicking a mild form of spinal muscular atrophy, provides a convenient drug screening platform highlighting new and pre-approved compounds. Hum Mol Genet. 2011;20:245–60.CrossRefPubMed
12.
Wolozin B, Gabel C, Ferree A, Guillily M, Ebata A. Watching worms whither: modeling neurodegeneration in C. elegans. Prog Mol Biol Transl Sci. 2011;100:499–514.PubMedCentralCrossRefPubMed
13.
Voisine C, Varma H, Walker N, Bates EA, Stockwell BR, Hart AC. Identification of potential therapeutic drugs for huntington’s disease using Caenorhabditis elegans. PLoS One. 2007;2:e504.PubMedCentralCrossRefPubMed
14.
Parker JA, Arango M, Abderrahmane S, Lambert E, Tourette C, Catoire H, et al. Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nat Genet. 2005;37:349–50.CrossRefPubMed
15.
Tauffenberger A, Julien C, Parker JA. Evaluation of longevity enhancing compounds against transactive response DNA-binding protein-43 neuronal toxicity. Neurobiol Aging. 2013;34:2175–82.CrossRefPubMed
16.
Karuppagounder SS, Pinto JT, Xu H, Chen HL, Beal MF, Gibson GE. Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer’s disease. Neurochem Int. 2009;54:111–8.PubMedCentralCrossRefPubMed
17.
Bizat N, Peyrin JM, Haik S, Cochois V, Beaudry P, Laplanche JL, et al. Neuron dysfunction is induced by prion protein with an insertional mutation via a Fyn kinase and reversed by sirtuin activation in Caenorhabditis elegans. J Neurosci. 2010;30:5394–403.CrossRefPubMed
18.
Kashyap SS, Johnson JR, McCue HV, Chen X, Edmonds MJ, Ayala M, et al. Caenorhabditis elegans dnj-14, the orthologue of the DNAJC5 gene mutated in adult onset neuronal ceroid lipofuscinosis, provides a new platform for neuroprotective drug screening and identifies a SIR-2.1-independent action of resveratrol. Hum Mol Genet. 2014;23:5916–27.PubMedCentralCrossRefPubMed
19.
Noskova L, Stranecky V, Hartmannova H, Pristoupilova A, Baresova V, Ivanek R, et al. Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis. Am J Hum Genet. 2011;89:241–52.PubMedCentralCrossRefPubMed
20.
Benitez BA, Alvarado D, Cai Y, Mayo K, Chakraverty S, Norton J, et al. Exome-sequencing confirms DNAJC5 mutations as cause of adult neuronal ceroid-lipofuscinosis. PLoS One. 2011;6:e26741.PubMedCentralCrossRefPubMed
21.
Velinov M, Dolzhanskaya N, Gonzalez M, Powell E, Konidari I, Hulme W, et al. Mutations in the gene DNAJC5 cause autosomal dominant Kufs disease in a proportion of cases: study of the Parry family and 8 other families. PLoS One. 2012;7:e29729.PubMedCentralCrossRefPubMed
22.
Cadieux-Dion M, Andermann E, Lachance-Touchette P, Ansorge O, Meloche C, Barnabe A, et al. Recurrent mutations in DNAJC5 cause autosomal dominant Kufs disease. Clin Genet. 2013;83:571–5.CrossRefPubMed
23.
Zinsmaier KE, Eberle KK, Buchner E, Walter N, Benzer S. Paralysis and early death in cysteine string protein mutants of Drosophila. Science. 1994;263:977–80.CrossRefPubMed
24.
Chamberlain LH, Burgoyne RD. Cysteine-string protein: the chaperone at the synapse. J Neurochem. 2000;74:1781–9.CrossRefPubMed
25.
Sharma M, Burre J, Sudhof TC. CSPalpha promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity. Nat Cell Biol. 2011;13:30–9.CrossRefPubMed
26.
Sharma M, Burre J, Sudhof TC. Proteasome inhibition alleviates SNARE-dependent neurodegeneration. Sci Transl Med. 2012;4:147ra113.CrossRefPubMed
27.
Burgoyne RD, Morgan A. Chaperoning the SNAREs: a role in preventing neurodegeneration? Nat Cell Biol. 2011;13:8–9.CrossRefPubMed
28.
Fernandez-Chacon R, Wolfel M, Nishimune H, Tabares L, Schmitz F, Castellano-Munoz M, et al. The synaptic vesicle protein CSP alpha prevents presynaptic degeneration. Neuron. 2004;42:237–51.CrossRefPubMed
29.
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 U S A. 2003;100:9980–5.PubMedCentralCrossRefPubMed
30.
31.
Steger KA, Shtonda BB, Thacker C, Snutch TP, Avery L. The C. elegans T-type calcium channel CCA-1 boosts neuromuscular transmission. J Exp Biol. 2005;208:2191–203.PubMedCentralCrossRefPubMed
32.
Gems D, Riddle DL. Defining wild-type life span in Caenorhabditis elegans. J Gerontol A Biol Sci Med Sci. 2000;55:B215–9.CrossRefPubMed
33.
Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cocheme HM, Noori T, et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013;153:228–39.PubMedCentralCrossRefPubMed
34.
Murphy CT, McCarroll SA, Bargmann CI, Fraser A, Kamath RS, Ahringer J, et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature. 2003;424:277–83.CrossRefPubMed
35.
Henderson ST, Johnson TE. Daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol. 2001;11:1975–80.CrossRefPubMed
36.
37.
Kang ML, Kwon JS, Kim MS. Induction of neuronal differentiation of rat muscle-derived stem cells in vitro using basic fibroblast growth factor and ethosuximide. Int J Mol Sci. 2013;14:6614–23.PubMedCentralCrossRefPubMed
38.
Park SH, Kukushkin Y, Gupta R, Chen T, Konagai A, Hipp MS, et al. PolyQ proteins interfere with nuclear degradation of cytosolic proteins by sequestering the Sis1p chaperone. Cell. 2013;154:134–45.CrossRefPubMed
39.
Collins JJ, Evason K, Pickett CL, Schneider DL, Kornfeld K. The anticonvulsant ethosuximide disrupts sensory function to extend C elegans lifespan. PLoS Genet. 2008;4:e1000230.PubMedCentralCrossRefPubMed
40.
41.
Evason K, Huang C, Yamben I, Covey DF, Kornfeld K. Anticonvulsant medications extend worm life-span. Science. 2005;307:258–62.CrossRefPubMed
42.
Choi H, Schneider H, Klum S, Chandler-Brown D, Kaeberlein M, Shamieh L. UV-Photoconversion of ethosuximide from a longevity-promoting compound to a potent toxin. PLoS One. 2013;8:e82543.PubMedCentralCrossRefPubMed
43.
Cohen E, Bieschke J, Perciavalle RM, Kelly JW, Dillin A. Opposing activities protect against age-onset proteotoxicity. Science. 2006;313:1604–10.CrossRefPubMed
44.
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;20:1952–65.PubMedCentralCrossRefPubMed
45.
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 U S A. 2002;99:10417–22.PubMedCentralCrossRefPubMed
46.
Cohen E, Paulsson JF, Blinder P, Burstyn-Cohen T, Du D, Estepa G, et al. Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell. 2009;139:1157–69.PubMedCentralCrossRefPubMed
47.
Tepper RG, Ashraf J, Kaletsky R, Kleemann G, Murphy CT, Bussemaker HJ. PQM-1 complements DAF-16 as a key transcriptional regulator of DAF-2-mediated development and longevity. Cell. 2013;154:676–90.PubMedCentralCrossRefPubMed
48.
Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ, et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature. 2002;419:316–21.CrossRefPubMed
49.
Mojsilovic-Petrovic J, Nedelsky N, Boccitto M, Mano I, Georgiades SN, Zhou W, et al. FOXO3a is broadly neuroprotective in vitro and in vivo against insults implicated in motor neuron diseases. J Neurosci. 2009;29:8236–47.PubMedCentralCrossRefPubMed
50.
Jiang M, Wang J, Fu J, Du L, Jeong H, West T, et al. Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets. Nat Med. 2012;18:153–8.PubMedCentralCrossRef
51.
Pino E, Amamoto R, Zheng L, Cacquevel M, Sarria JC, Knott GW, et al. FOXO3 determines the accumulation of alpha-synuclein and controls the fate of dopaminergic neurons in the substantia nigra. Hum Mol Genet. 2014;23:1435–52.CrossRefPubMed
52.
53.
54.
Zhang Y, Chen D, Smith MA, Zhang B, Pan X. Selection of reliable reference genes in Caenorhabditis elegans for analysis of nanotoxicity. PLoS One. 2012;7:e31849.PubMedCentralCrossRefPubMed
55.
Benjamini Y, Hochberg Y. Controlling the false discovery rate - a practical and powerful approach to multiple testing. J R Stat Soc Ser B-Methodol. 1995;57:289–300.
Metadata
Title
Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression
Authors
Xi Chen
Hannah V. McCue
Shi Quan Wong
Sudhanva S. Kashyap
Brian C. Kraemer
Jeff W. Barclay
Robert D. Burgoyne
Alan Morgan
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2015
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-015-0046-3

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