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Neurotoxin-Induced Degeneration of Dopamine Neurons in Caenorhabditis Elegans

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Neurotoxin-Induced Degeneration of Dopamine Neurons in Caenorhabditis Elegans Neurotoxin-induced degeneration of dopamine neurons in Caenorhabditis elegans Richard Nass*†, David H. Hall‡, David M. Miller III†§, and Randy D. Blakely*†¶ Departments of *Pharmacology and §Cell Biology and †Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, TN 37232-6420; and ‡Center for Caenorhabditis elegans Anatomy, Albert Einstein College of Medicine, New York, NY 10461 Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved December 27, 2001 (received for review September 21, 2001) Parkinson’s disease is a complex neurodegenerative disorder char- vesicular packaging, and inactivation (16–19). Moreover, the acterized by the death of brain dopamine neurons. In mammals, genetics and cellular features of necrotic and apoptotic cell death dopamine neuronal degeneration can be triggered through expo- have been well described in C. elegans (20, 21), affording an sure to neurotoxins accumulated by the presynaptic dopamine opportunity to relate toxin-induced dopamine neuronal injury to transporter (DAT), including 6-hydroxydopamine (6-OHDA) and these pathways. 1-methyl-4-phenylpyridinium. We have established a system for the pharmacological and genetic evaluation of neurotoxin-induced Materials and Methods dopamine neuronal death in Caenorhabditis elegans. Brief (1 h) Strains and Maintenance. C. elegans strains were cultured on exposure of green fluorescent protein-tagged, living worms to bacterial lawns of either OP-50 or NA-22 at 22°C according to 6-OHDA causes selective degeneration of dopamine neurons. We standard methods (22). N2 Bristol is the wild-type strain. ced- demonstrate that agents that interfere with DAT function protect 1(e1735), ced-3(n717), ced-4(n1162), dpy-20(e1282), dpy- against 6-OHDA toxicity. 6-OHDA-triggered neural degeneration 17(e164), unc-13(e51), unc-30(e191), and unc79(e1068) strains does not require the CED-3͞CED-4 cell death pathway, but is were obtained from the Caenorhabditis Genetics Center (Uni- abolished by the genetic disruption of the C. elegans DAT. versity of Minnesota, Minneapolis). The dat-1(ok157) strain was a gift of J. Duerr and J. Rand (Oklahoma Medical Research transporter ͉ genetics ͉ catecholamine ͉ Parkinson’s disease ͉ apoptosis Foundation, Oklahoma City). The daf-7::gfp line (DR2022) was a gift from D. Riddle (University of Missouri, Columbia) (23). arkinson’s disease (PD), a severe movement disorder char- The tph-1::gfp (GR1321) was a gift of J. Sze (University of acterized by resting tremor, spasticity, and an inability to California, Irvine) and G. Ruvkun (Massachusetts General P ced initiate movement, arises from the progressive, irreversible loss Hospital, Boston). All 6-OHDA assays involving mutants were performed in genetic backgrounds containing closely of dopamine neurons in the substantia nigra pars compacta (1). linked recessive markers to aid in identifying homozygous ced Although rare genetic forms of PD have been identified (2, 3), mutants: ced-1(e1735) unc-13(e51) (MT3608), ced-3(n717) unc- the molecular determinants of dopamine neuron vulnerability 30(e191) dpy-20(e1282) (MT5729), and ced-4(n1162) unc- and cell death in the majority of PD cases remain as yet ill 79(e1068) (MT2550). 6-OHDA experiments involving ced- defined. Current hypotheses involve environmental toxin expo- 4(n1162) dpy-17(e164) (MT2551) give qualitatively similar sure, the increased generation of reactive oxygen species, and results as ced-4(n1162) unc-79(e1068). ced-3(n717) and ced- inhibition of mitochondrial electron transport (1, 4). How these 4(n1162) are likely null and͞or strong loss-of-function alleles, events are targeted to dopamine neurons is unresolved. Dopa- respectively (24–26). ced-3 and ced-4 mutant lines show super- mine itself is a highly oxidizable substance, and its uncontrolled numerary dopamine neurons, further confirming the homozy- metabolism or improper sequestration may trigger oxidative gosity of the ced mutations (data not shown). damage, supporting cell death (5, 6). The best-studied rodent and primate models of PD use the Plasmid Construction. The DAT-1 transcriptional green fluores- neurotoxins 6-hydroxydopamine (6-OHDA) or 1-methyl-4- cent protein (GFP) fusion (Pdat-1::GFP) was created by PCR phenyl-1,2,3,6-tetrahydropyridine (MPTP), and more recently amplification of the DAT-1 regulatory region found in cosmid the pesticide rotenone, to chemically ablate dopamine neurons T23G5.5 (refs. 27 and 28; T. Ishihara and I. Katsura, personal in vivo (1, 7, 8). 6-OHDA and the reactive metabolite of MPTP, ϩ communication). The amplified product, containing 716 bp MPP (1-methyl-4-phenylpyridinium), are selectively accumu- immediately upstream of the initiating codon ATG, was digested lated by dopamine neurons through preynaptic dopamine trans- with HindIII and BamHI, and the resultant 0.7-kb fragment was porters (DATs), causing an increase in reactive oxygen species ͞ cloned into the HindIII and BamHI sites of pPD95.73 (gift from and or mitochondrial dysfunction, and that may thereby induce A. Fire, Carnigie Institute of Washington, Baltimore), now neuritic damage and cell death (9–11). 6-OHDA is particularly called pRB490. The DAT-1 translational GFP fusion intriguing as it is found in brain and urine samples of PD patients, (Pdat-1::DAT-1::GFP) was created by PCR amplification from suggesting it may be an endogenous component of PD patho- cosmid T23G5.5 by using the above promoter to ϩ0.4 kb from genesis (12–14). Although mammalian models afford the highest the initiating codon. The amplified product, which contained the degree of physiologic and behavioral correlates to PD, genetic manipulations that might define molecular pathways supporting dopamine neuron vulnerability, death, and protection are lim- This paper was submitted directly (Track II) to the PNAS office. ited and often impractical. We reasoned that the presence of Abbreviations: PD, Parkinson’s disease; DAT, dopamine transporter; GFP, green fluorescent dopamine neurons in the nematode Caenorhabditis elegans (15), protein; CEP, cephalic sensilla; 6-OHDA, 6-hydroxydopamine; ADE, anterior deirids; PDE, a transparent organism with well-developed genetic and trans- posterior deirids; EM, electron microscopy; AA, ascorbic acid. genic methodologies, might afford new opportunities to inves- ¶To whom reprint requests should be addressed at: Center for Molecular Neuroscience, 417 Preston Research Building, Vanderbilt University School of Medicine, Nashville, TN 37232- tigate the molecular basis of dopamine neuron degeneration. At 6420. E-mail: [email protected]. a molecular level, all of the fundamental components involved in The publication costs of this article were defrayed in part by page charge payment. This dopamine neurotransmission are present in the nematode, in- article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. cluding the proteins responsible for dopamine biosynthesis, §1734 solely to indicate this fact. 3264–3269 ͉ PNAS ͉ March 5, 2002 ͉ vol. 99 ͉ no. 5 www.pnas.org͞cgi͞doi͞10.1073͞pnas.042497999 Downloaded by guest on October 1, 2021 first exon and intron and part of exon 2, was digested with as positive for dopamine neurodegeneration. For dopamine HindIII and SpHI, and the resultant 1.2-kb fragment was cloned neurons analyses using the cat-2 promoter, the neurons were into the HindIII and SpHI sites of pPD95.73l (gift from A. Fire), considered positive for degeneration if the any of the four CEP now called pRB491. The remainder of the DAT-1 coding region dendritic endings in the nose were absent. For the was amplified by PCR at ϩ1.1 kb from the initiation codon to tph-1::gfp-expressing cells, the neurons were scored as positive if immediately before the TGA stop codon by using the DAT-1 either of the NSM cell bodies were damaged or missing. For the vector pRB235 [previously called pCeDAT2 (16)], as the tem- unc-4::gfp-expressing cells, the neurons were scored as positive plate. The PCR fragment was digested with SpHI and BamHI, if anteriorly directed axons from the retrovesicular ganglion and the resultant 1.8-kb fragment was ligated in-frame into the motor neurons, SABVL and SABVR, were absent. For the same sites in pRB491, now called pRB493. For mammalian cell daf-7::gfp-expressing cells, the neurons were scored as positive if expression studies, DAT-1 cDNA was subcloned from pCeDAT2 the ASI cell bodies or processes could not be seen. (16) into pcDNA3 (Invitrogen) at KpnI and NotI sites, creating pRB454. Microscopy. Confocal images were captured with either a Zeiss LSM 410 or 510 confocal microscope. Z-series images were COS-7 Expression of DAT-1. Functional expression of DAT-1 cDNA collected by optical sectioning at intervals of Ϸ1 ␮m. Epifluo- was obtained in transiently transfected COS cells by using the rescence micrographs were taken with Elite 400 film (Kodak) Fugene 6 Transfection reagent (Roche Diagnostics) following and a 35-mm camera mounted on a Zeiss Axioplan microscope the manufacturer’s protocol. Briefly, COS cells were cultured in with a ϫ63 or ϫ40 Plan Apo, N.A. 1.4 objective. All image DMEM supplemented with 10% FBS (HyClone), 2 mM L- processing and montage assembly were performed with Adobe glutamine, 100 units͞ml penicillin, and 100 mg͞ml streptomy- PHOTOSHOP. cin. One day before transfections, 1 ϫ 105 cells were plated in For electron microscopy (EM), treated animals were fixed at 24-well tissue culture plates. Cells were transfected with pRB454, Ϸ60 h after exposure to 6-OHDA, as described above. Primary and 48 h later cells were harvested and processed for [3H]do- fixation was in buffered aldehydes (2.5% glutaraldehyde plus pamine transport as described (16), using [3H]dopamine at 50 1.0% paraformaldehyde), followed by secondary fixation in 1% nM, assaying 5 min at 37°C. Nonspecific transport, defined as osmium tetroxide plus 0.5% potassium ferrocyanide, and en bloc accumulation in vector-transfected cells, was subtracted from the staining with 1% uranyl acetate (UAc) (20).
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