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PRIMER

Physicists and astronomers have long positedthe concept of a ‘wormhole’ as a means ofrapid interstellar travel by analogy with howa worm could eat a hole from one end of anapple, through the center to the other end,and create a shortcut through the interven-ing space. Unfortunately, bending the fabricof space and time is not typically considereda viable option to more rapidly explore curesfor neurodegenerative diseases (and wouldlikely result in a poorly received grant appli-cation). The biological equivalent of thespace exploration program, the humangenome project, has unleashed an age ofgenomic, proteomic, metabolomic, andbioinformatic analyses that has generated awealth of datasets primed for subsequent dis-covery. This exponential growth demandsthe development of functional means forexploiting this treasure trove of biologicalinformation. In this regard, biomedicalresearchers are literally turning to a worm to

accelerate the path toward therapeuticadvances and get to the core of mechanismsunderlying Parkinson’s disease (PD).

While drugs to treat the symptoms of PDhave been prescribed for decades (e.g. L-DOPA), an unmet need for innovative strate-gies to discern disease etiology and treat-ments that either halt or reverse progressionremains. Application of a microscopic nema-tode roundworm toward gaining insightsinto a human neurodegenerative disordermay seem impractical; yet, C. elegans affordsmany advantages for such research, as it hasa defined cell lineage, completed genomesequence, and lifespan of only 2 weeks. Asopposed to the human brain, which is esti-mated to have over 100 billion nerve cells,this nematode contains precisely 302 neu-rons for which a defined neuronal connec-tivity map has been determined. In thisregard, C. elegans is ideal for investigation ofdiseases associated with neuronal dysfunc-

tion and ageing, and represents a model sys-tem that is poised to bridge the gap betweenbasic and translational research.

Interpretation of disease-associated dataobtained in invertebrate systems requiresdownstream validation in mammals prior toestablishing the therapeutic significance ofany findings. The likelihood of a positive out-come is significant, however, due to the evo-lutionary conservation of metazoan genomes.For example, human homologs have beenidentified for at least 50% of C. elegans genes.Remarkably, these include all orthologs ofreported genes linked to familial forms of PD(Fig. 1), with the one exception being the geneencoding α-synuclein. Despite this differ-ence, ectopic overexpression of both wildtypeand mutant (A53T) human α-synuclein ledto motor deficits or DA neuron loss in C. ele-gans (Lasko et al., 2003). Subsequent reportsalso demonstrated phenotypic changes asso-ciated with driving α-synuclein expressionfrom a variety of pan-neuronal and specificneuronal promoters (Cao et al., 2005; Ved etal., 2005; Kuwahara et al., 2006). The trans-lational utility of C. elegans is perhaps bestdemonstrated by the characterization of con-served neuroprotective genes that block α-synuclein-associated degeneration in nema-todes (Cooper et al., 2006; Gitler et al., 2008;Hamamichi et al., 2008).

The rich, 40-year history of C. elegansgenetics provides a legacy of behavioral andneuroanatomical information thatresearchers draw upon to elucidate rela-tionships between gene function and PD-associated mechanisms (Bargmann, 1998).Using traditional genetic suppressor andenhancer screening, investigators havebegun to dissect genetic contributors to DAneuron development and function (Chaseet al., 2004). A limbless simple invertebratewill certainly never recapitulate the pheno-typic behaviors associated with the tremorand dyskinesia of PD, yet this nematodedoes afford opportunities for accurate quan-tification of factors that influence DA neu-ron survival. Loss of DA neurons in C. ele-gans is not lethal and leads only to a subtle

1Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA2Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics,University of Alabama at Birmingham, Birmingham, AL 35294, USA*Author for correspondence (e-mail: gcaldwel@bama.ua.edu)

Disease Models & Mechanisms 1, 32-36 (2008) doi:10.1242/dmm.000257

Traversing a wormhole to combat Parkinson’sdiseaseGuy A. Caldwell1,2,* and Kim A. Caldwell1,2

Human movement disorders represent a significant and unresolved societalburden. Among these, the most prevalent is Parkinson’s disease (PD), a disorderafflicting millions worldwide. Despite major advances, stemming primarily fromhuman genetics, there remains a significant gap in our understanding of whatfactors underlie disease susceptibility, onset, and progression. Innovative strategiesto discern specific intracellular targets for subsequent drug development areneeded to more rapidly translate basic findings to the clinic. Here we briefly reviewthe recent contributions of research using the nematode roundwormCaenorhabditis elegans as a model system for identifying and characterizing geneproducts associated with PD. As a microscopic but multicellular and geneticallytractable animal with a well-defined nervous system and an experimentallytenable lifespan, C. elegans affords significant advantages to researchers attemptingto determine causative and therapeutic factors that influence neuronal dysfunctionand age-associated neurodegeneration. The rapidity with which traditional genetic,large-scale genomic, and pharmacological screening can be applied to C. elegansepitomizes the utility of this animal for disease research. Moreover, with maturebioinformatic and functional genomic data readily available, the nematode is wellpositioned to play an increasingly important role in PD-associated discoveries.

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behavioral deficit where affected animalsdisplay an inability to discriminate localmechanosensory cues (Sawin et al., 2000).Unfortunately, this behavior, while quan-tifiable, is not robust enough to be easilyused in extensive screening paradigms.

Mammalian and primate modelingapproaches to PD have traditionallyinvolved use of neurotoxins to induce DAneuron loss and evaluate the consequencesof neurodegeneration. Among these tox-ins are 1-methyl 4-phenyl 1,2,3,6-tetrahy-dropyridine (MPTP), 6-hydroxydopamine(6-OHDA), as well as the pesticidesrotenone and paraquat. Worms are sus-ceptible to these toxins (Nass et al., 2002;Braungart et al., 2004; Cao et al., 2005);moreover, the defined and transparentneuroanatomy of C. elegans includes pre-cisely eight neurons that produce DA,thereby enabling an unparalleled level ofquantitative analysis of neurodegenerationand protection by use of fluorescent pro-tein labeling (Fig. 2). Furthermore, theseanimals can be evaluated in specific geneticor transgenic backgrounds to screen forfactors that confer either neuroprotectionor enhancement of degeneration. One neu-roprotective gene product termed TOR-2,

a human torsinA-related protein with mol-ecular chaperone-like activity (Caldwell etal., 2008), was shown to deter multipleforms of toxic insults to DA neurons,including 6-OHDA, excess intracellularDA production, and α-synuclein overex-pression (Cao et al., 2005). The neuropro-tective capacity of torsin-like proteins ren-ders them intriguing candidates forsubsequent drug targeting and validation

in mammalian systems, where humantorsinA is endogenously expressed in DAneurons (Augood et al., 1998).

Directed and comprehensive screenshave been undertaken to define chemicaland genetic effectors of worm DA neuronsensitivity to 6-OHDA (Nass et al., 2005;Maranova and Nichols, 2007). These stud-ies identified a collection of intragenicmutations in the gene sequence encodingthe key protein required for DA reuptakeinto presynaptic neurons, the DA trans-porter (DAT-1). Structural and functionalrelationships revealed through this workhave implications not only for PD, but alsofor other disorders associated with DATfunction (e.g. depression, ADHD). It hasalso been shown that worm dat-1 knock-out mutants exhibit diminished α-synu-clein-dependent degeneration, which indi-cates a possible role for DAT in maintainingan important balance of intraneuronal lev-els of DA, the dysregulation of which maycontribute to cytotoxicity (Cao et al., 2005).

Elegant studies in Drosophila havedemonstrated the capacity for model sys-tems to reveal unsuspected relationshipsbetween PD gene products, such as PINK1and Parkin, and their impact on mitochon-drial integrity and morphology (Clark et al.,2006; Park et al., 2006; Poole et al., 2008).Likewise, the ability of worm research to linkgenotype to phenotype in this manner isaccelerating our understanding of the under-lying nature of PD. Ved et al. investigated thefunctional consequences of rotenone-induced stress and reported that pan-neu-ronal overexpression of human α-synuclein(wild-type or A53T mutant), RNAi knock-down of a C. elegans DJ-1 ortholog(B0432.2), or a deletion mutant of the C. ele-gans parkin ortholog (pdr-1), all producedsimilar patterns of mitochondrial vulnera-bility in response to pharmacological chal-lenges associated with complex I inhibition(Ved et al., 2005). Furthermore, the effect ofrotenone, which led to mortality in these ani-mals, was more severe in α-synuclein-expressing strains and the pdr-1 deletionmutant than in control animals of wild-typebackground. Initial work on worm PDR-1revealed that this Parkin ortholog, an E3ubiquitin ligase, cooperates with conserveddegradation machinery to mediate ubiqui-tin conjugation (Springer et al., 2005). Co-expression of C. elegans pdr-1 and α-synu-clein variants in human cell cultures showedthat a truncated protein derived from an

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Parkinson’s disease PRIMER

Fig. 1. PD-associated gene products and their prospective sites of cellular function. PD ishypothesized to be a consequence of the dysfunction of intersecting and compensatory proteindegradation components, including those associated with the lysosome and autophagy, as well as thoseassociated with the ubiquitin proteasome system (UPS). Inefficient clearance and enhanced misfolding, orexpression, of �-synuclein has been shown to block intracellular trafficking and increase cytotoxicity.Accordingly, mutations in Parkin (an E3 ubiquitin ligase), ubiquitin C-terminal hydrolase-1 (UCHL-1), aswell as in a lysosomal ATPase termed ATP13A2 and the Gaucher’s disease-related proteinglucocerebrosidase (GBA), have further implicated protein degradation pathways in PD. PD-associatedmutations in genes linked with mitochondrial function, such as those encoding DJ-1 and the PTEN-induced kinase (PINK1), presumably affect the production of reactive oxygen species (ROS), whichaccelerate protein damage and neurodegeneration. While mutations in the leucine-rich repeat kinase 2(LRRK2) protein now represent the most common heritable cause of PD, the function of this large, 2527amino acid multidomain-containing protein remains undefined.

Fig. 2. Anterior dopamine neurons of C. elegans.Cell bodies and processes of the six anterior DAneurons including two pairs of the CEP (cephalic)neurons and one pair of ADE (anterior deirid)neurons, as illuminated using GFP driven from thedopamine transporter promoter (Pdat-1::GFP). Twoadditional DA neurons (PDEs) are found in theposterior (not shown).

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in-frame pdr-1 (lg103) deletion allele causesaggregation of α-synuclein, similar to Parkinvariants isolated from PD patients. Thisaltered gene product also resulted in pro-teotoxicity and hypersensitivity to ER stress(Springer et al., 2005). These examplesdemonstrate how mutant analysis in C. ele-gans offers a powerful strategy for uncover-ing functional relationships between geneproducts with key roles in PD pathogenesisin mammalian cells.

C. elegans has been recently used to showa protective role for human LRRK2 (leucine-rich repeat kinase 2) against mitochondrialtoxicity induced by rotenone, an effectpotentiated by knockdown of an endoge-nous worm ortholog, lrk-1 (Wolozin et al.,2008). These data are surprising when con-sidering a PD-associated G2019S mutantversion of LRRK2 that exhibits increasedkinase activity was also found to be pro-tective; kinase activity has been suggestedto contribute to the pathogenesis associatedwith LRRK2 neurotoxicity (West et al.,2007). An initial report on lrk-1 function inC. elegans indicated a role for the productof this gene in establishing neuronal polar-ity (Sakaguchi-Nakashima et al., 2007). Asmutations in LRRK2 now represent themost common genetic cause of PD (Hau-garvoll et al., 2008), further insights gleanedfrom C. elegans on this important, yet rel-atively uncharacterized, protein family willundoubtedly be informative.

The capacity for genomic-scale screeninghas brought C. elegans to the forefront ofmodern functional analysis (Kamath andAhringer, 2003). In contrast to mammals,where individual knockouts of mice areexpensive and time consuming, worms arean efficient and economical alternative.Hamamichi et al. took a hypothesis-drivenapproach toward identification of putativegenetic modifiers of PD via a multi-tieredscreen for C. elegans genes that impact themisfolding of transgenic human α-synu-clein, as well as neuroprotection, in vivo(Hamamichi et al., 2008). This study encom-passed RNAi knockdown of nearly 900bioinformatically prioritized gene targets,comprising components of cellular pathwaysimplicated in protein folding or degradation,as well as gene products that are either co-expressed or interact with worm orthologsof familial PD genes. From this varied, butbiased, ‘guilt by association’ list of targets,20 candidate genes emerged as having thegreatest propensity to influence α-synuclein

misfolding. Internal validation was evidentwithin this short list, as included were theworm homologs of two established recessivePD genes (DJ-1, PINK1), as well as a gene(ULK2) shown to be one of only six identi-fied in a genome-wide association study ofpolymorphisms in PD patients (Fung et al.,2006). Importantly, overexpression of selectcDNAs in C. elegans DA neurons revealedthat five of seven gene products tested, cho-sen from the primary effectors of α-synu-clein misfolding identified in the RNAiscreen, exhibited significant protection fromage- and dose-dependent neurodegenera-tion induced by α-synuclein (Hamamichi etal., 2008). Thus, application of C. elegans inthis context uncovered functionally evalu-ated targets identified by the two primaryclinical criteria associated with PD: α-synu-clein accumulation and DA neurodegener-ation.

These genes, which included uncharac-terized proteins, as well as regulators ofautophagy, lysosomal function, cellular traf-ficking, and G-protein signaling, now repre-sent outstanding candidates for strategicallytargeted drug development and validation inmammalian systems. A more recently con-ducted unbiased genome-wide RNAi screenfor genetic factors that influence α-synucleininclusion formation in C. elegans also yieldedan over-representation of genes encodingcomponents of vesicular trafficking, as wellas specific age-associated genes (e.g. sir-2.1)(van Ham et al., 2008). Similar validation ofthe effect that these additional targets mayhave on DA neuron survival will likely revealfunctionally significant relationships as well.Associations between PD and lysosomaldegradation are of growing interest follow-ing the identification of a lysosomal ATPase,ATP13A2 (PARK9), as a gene product linkedto hereditary early-onset PD with dementia(Ramirez et al., 2006), in addition to the dis-covery of a higher incidence of PD in patientswith mutations in the Gaucher’s disease-associated gene, GBA, encoding the lysoso-mal storage-enzyme glucocerebrosidase.(Aharon-Peretz et al., 2004; Clark et al.,2007). It is easy to envision an expansion ofsuch gene-specific data and the applicationof C. elegans toward investigating the func-tional consequences of single-nucleotidepolymorphisms (SNPs) found in human pop-ulations, as these may potentially lead togenetic biomarkers of disease susceptibility.

The burgeoning promise that a micro-scopic worm may contribute toward the goal

of drug discovery for PD has become a tan-gible reality. Containing a rudimentary ner-vous system, unlike single-celled organisms,but more amenable to transgenic analysisand drug screening than mammals, C. ele-gans serves as an excellent intermediary bot-tleneck in translational research pipelines tocharacterize therapeutic gene and drug tar-gets across animal models. Concerted effortstoward therapeutic development have beeninitiated that exploit the high-throughputscreening capabilities of yeast cells to definenumerous gene targets of interest, followedby subsequent evaluation of their neuropro-tective capacity in worms, fruit flies and ratneuronal cultures (Cooper et al., 2006; Gitleret al., 2008). This approach has alreadyrevealed that overproduction of α-synucleinleads to a cytotoxic blockage in intracellularvesicular trafficking that can be alleviated byspecific members of the Rab protein family(Cooper et al., 2006; Gitler et al., 2008).Thus, through the employment of a combi-nation of powerful model systems, not onlyhas a prospective cellular cause of PD beenilluminated, but targeted screens for smallmolecules that protect against underlyingfunctional aspects of neurodegeneration arenow possible.

When envisioning future directionswhereby C. elegans will benefit PD research,several inescapable advantages of this modelsystem should be considered. The most obvi-ous of these is the well-established use of theworm for investigating mechanisms of aging(Kenyon, 2005). Indeed, the only definitiverisk factor for PD is aging, where PD symp-tomatically affects over 2% of people aboveage 65. Extensive studies on worm longevitymutants (e.g. daf-2 or age-1) have demon-strated that evolutionarily conserved mech-anisms are shared between invertebrates andmammals. Microarray and genomic-scaleRNAi analyses conducted in age-extendingbackgrounds have yielded significant insightsinto gene sets that implicate dietary restric-tion and insulin-like signaling pathways ascrucial mediators of lifespan (Murphy et al.,2003; Panowski et al., 2007). The vital, butpoorly understood, interface between agingand age-associated neurodegenerative dis-ease represents an exciting frontier that isreadily explored using C. elegans.

Furthermore, in the advent of themicroRNA (miRNA) revolution, our nascentunderstanding of putative regulatory rolesfor miRNAs in neuron function will likelysoon interface with our understanding of

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neurological disease and PD (Kosik, 2006;Kim et al., 2007). Considering the pioneer-ing role worm research has played in defin-ing miRNA function, a universe of possibil-ities exist, as worm researchers arewell-poised to explore relationships betweenmiRNAs, ageing and neuroprotective geneactivity (Ibanez-Ventoso, 2007).

Finally, although the primary advances inPD etiology have come through humangenetics, the largely idiopathic nature of PDremains linked to inexplicable environmen-tal causes. C. elegans research into innateimmunity and cellular stress response hasalready provided mechanistic insights intoorganismal defenses and environmentalinfluences on homeostasis (Kim et al., 2002;Mohri-Shiomi and Garsin, 2008). An expan-sion of neurotoxicity studies conducted in C.elegans is warranted and may yield a greaterunderstanding of the interplay betweengenetic composition and environmental fac-tors such as heavy metals, pesticides andother untested exposures.

The worm is unquestionably a powerfulsystem, yet it has its limitations: theanatomical and functional connectivity ofthe neuronal circuitry within this simplenematode cannot recapitulate the complexfeatures of mammalian dopamine neuronsor mimic the precise behavioral deficitsassociated with their loss. Likewise, as acautionary caveat to inferring conservationof function from genetic interaction data,Tischler et al. demonstrated that syntheticlethal gene interactions between yeast and

worm genes are not significantly conserved(Tischler et al., 2008). In this context, as themarch toward systems biology proceedsand integrated analyses of gene or proteinactivity continue to lead to an increasingnumber of complex datasets, our ability toeventually define causes and cures willdepend on functional strategies for wadingthrough the emerging ‘information over-load’. Science will benefit from the efficientmanner by which C. elegans research cancontribute to the quest for translational andpersonalized medical breakthroughs, byboldly going where no worm has gonebefore.COMPETING INTERESTSThe authors declare no competing financial interests.

REFERENCESAharon-Peretz, J., Rosenbaum, H. and Gershoni-

Baruch, R. (2004). Mutations in the glucocerebrosidasegene and Parkinson’s disease in Ashkenazi Jews. NewEngl. J. Med. 351, 1972-1977.

Augood, S. J., Penney, J. B., Jr, Friberg, I. K.,Breakefield, X. O., Young, A. B., Ozelius, L. J. andStandaert, D. G. (1998). Expression of the early-onsettorsion dystonia gene (DYT1) in human brain. Ann.Neurol. 43, 669-673.

Bargmann, C. I. (1998). Neurobiology of the C. elegans.Genome Science 282, 2028-2033.

Braungart, E., Gerlach, M, Riederer, P., Baumeister, R.and Hoener, M. C. (2004). Caenorhabditis elegansMPP+ model of Parkinson’s disease for high-throughput drug screenings. Neurodegener Dis. 1, 175-183.

Caldwell, G. A., Cao, S., Sexton, E. G., Gelwix, C. C.,Bevel, J. P. and Caldwell, K. A. (2003). Suppression ofpolyglutamine-induced protein aggregation inCaenorhabditis elegans by torsin proteins. Hum. Molec.Genet. 12, 307-319.

Cao, S., Gelwix, C. C., Caldwell, K. A. and Caldwell, G.A. (2005). Torsin-mediated protection from cellularstress in the domaminergic neurons of Caenorhabditiselegans. J. Neurosci. 12, 3801-3812.

Chase, D. L., Pepper, J. S. and Koelle, M. R. (2004).Mechanism of extrasynaptic dopamine signaling inCaenorhabditis elegans. Nat. Neurosci. 7, 1096-1103.

Clark, I. E., Dodson, M. W., Jiang, C., Cao, J. H., Huh, J.R., Seol, J. H., Yoo, S. J., Hay, B. A. and Guo, M.(2006). Drosophila pink1 is required for mitochondrialfunction and interacts genetically with parkin. Nature441, 1162-1166.

Clark, L. N., Ross, B. M., Wang, Y., Mejia-Santana, H.,Harris, J., Louis, E. D., Cote, L. J., Andrews, H., Fahn,S., Waters, C. et al. (2007). Mutations in theglucocerebrosidase gene are associated with early-onset Parkinson’s disease. Neurology 69, 1270-1277.

Cooper, A. A., Gitler, A. D., Cashikar, A., Haynes, C. M.,Hill, K. J., Bhullar, B., Liu, K., Xu, K., Strathearn, K. E.,Liu, F. et al. (2006). Alpha-synuclein blocks ER-Golgitraffic and Rab1 rescues neuron loss in Parkinson’smodels. Science 313, 324-328.

Fung, H. C., Scholz, S., Matarin, M., Simon-Sanchez, J.,Hernandez, D., Britton, A., Gibbs, J. R., Langefeld,C., Stiegert, M. L., Schymick, J. et al. (2006). Genome-wide genotyping in Parkinson’s disease andneurologically normal controls: first stage analysis andpublic release of data. Lancet 5, 911-916.

Gitler, A. D., Bevis, B. J., Shorter, J., Strathearn, K. E.,Hamamichi, S., Su, L. J., Caldwell, K. A., Caldwell, G.

A., Rochet, J. C., McCaffery, J. M. et al. (2008). TheParkinson’s disease protein alpha-synuclein disruptscellular Rab homeostasis. Proc. Natl. Acad. Sci. USA 105,145-150.

Hamamichi, S., Rivas, R. N., Knight, A. L., Cao, S.,Caldwell, K. A. and Caldwell, G. A. (2008).Hypothesis-based RNAi screening identifiesneuroprotective genes in a Parkinson’s disease model.Proc. Natl. Acad. Sci. USA 105, 728-733.

Kamath, R. S. and Ahringer, J. (2003). Genome-wideRNAi screening in Caenorhabditis elegans. Methods 30,313-321.

Kenyon, C. (2005). The plasticity of aging: insights fromlong-lived mutants. Cell 120, 449-460.

Kim, D. H., Feinbaum, R., Alloing, G., Emerson, F. E.,Garsin, D. A., Inoue, H., Tanaka-Hino, M., Hisamoto,N., Matsumoto, K., Tan, M. W. et al. (2002). Aconserved p38 MAP kinase pathway in Caenorhabditiselegans innate immunity. Science 297, 623-626.

Kim, J., Inoue, K., Ishii, J., Vanti, W. B., Voronov, S. V.,Murchison, E., Hannon, G. and Abeliovich, A. (2007).A microRNA feedback circuit in midbrain dopamineneurons. Science 317, 1220-1224.

Kosik, K. S. (2006). The neuronal microRNA system. Nat.Rev. Neurosci. 7, 911-920.

Kuwahara, T., Koyama, A., Gengyo-Ando, K., Masuda,M., Kowa, H., Tsunoda, M., Mitani, S. and Iwatsubo,T. (2006). Familial Parkinson mutant �-synucleincauses dopamine neuron dysfunction in transgenicCaenorhabditis elegans. J. Biol. Chem. 281, 334-340.

Lasko, M., Vartiainen, S., Moilanen, A.-M., Sirvio, J.,Thomas, J. H., Nass, R., Blakley, R. D. and Wong, G.(2003). Dopaminergic neuronal loss and motor deficitsin Caenorhabditis elegans overexpressing human α-synuclein. J. Neurochem. 86, 165-172.

Haugarvoll, K., Rademakers, R., Kachergus, J. M.,Nuytemans, K., Ross, O. A., Gibson, J. M., Tan, E. K.,Gaig, C., Tolosa, E., Goldwurm, S. et al. (2008). Lrrk2R1441C parkinsonism is clinically similar to sporadicParkinson disease. Neurology 70, 1456-1460.

Ibanez-Ventoso, C., Yang, M., Guo, S., Robins, H.,Padgett, R. W. and Driscoll, M. (2006). ModulatedmicroRNA expression during adult lifespan inCaenorhabditis elegans. Aging Cell 5, 235-246.

Maranova, M. and Nichols, C. D. (2007). Identification ofneuroprotective compounds of Caenorhabditis elegansdopaminergic neurons against 6-OHDA. J. Mol.Neurosci. 31, 127-137.

Mohri-Shiomi, A. and Garsin, D. A. (2008). Insulinsignaling and the heat shock response modulateprotein homeostasis in the Caenorhabditis elegansintestine during infection. J. Biol. Chem. 283, 194-201.

Murphy, C. T., McCarroll, S. A., Bargmann, C. I., Fraser,A., Kamath, R. S., Ahringer, J., Li, H. and Kenyon, C.(2003). Genes that act downstream of DAF-16 toinfluence the lifespan of Caenorhabditis elegans.Nature 424, 277-283.

Nass, R., Hahn, M. K., Jessen, T., McDonald, P. W.,Carvelli, L. and Blakely, R. D. (2005). A geneticscreen in Caenorhabditis elegans for dopamineneuron insensitivity to 6-hydroxydopamine identifiesdopamine transporter mutants impacting transporterbiosynthesis and trafficking. J. Neurochem. 94, 774-785.

Nass, R., Hall, D. H., Miller, D. M., 3rd and Blakely, R. D.(2002). Neurotoxin-induced degeneration of dopamineneurons in Caenorhabditis elegans. Proc. Natl. Acad. Sci.USA 99, 3264-3269.

Panowski, S. H., Wolff, S., Aguilaniu, H., Durieux, J.and Dillin, A. (2007). HA-4/Foxa mediates diet-restriction-induced longevity of C. elegans. Nature 447,550-555.

Park, J., Lee, S. B., Lee, S., Kim, Y., Song, S., Kim, S.,Bae, E., Kim, J., Shong, M., Kim, J. M. et al. (2006).

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Advantages of C. elegansas a model for Parkinson’sdisease•

All orthologs of genes linked to familial PDhave been identified in C. elegans, except α-synuclein

•Ectopic overexpression of α-synuclein hasneurotoxic effects in C. elegans, which areblocked by neuroprotective genes

•C. elegans has a simple nervous system (302neurons compared with over 100 billion inhumans) that is amenable to quantitativeanalysis of neurodegeneration

•C. elegans is susceptible to toxins commonlyused to model neurodegeneration

•C. elegans studies predict relationshipsbetween cellular signaling, trafficking andprotein degradation pathways, which arebeing tested for their susceptibility totargeted drug development for PD

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Mitochondrial dysfunction in Drosophila PINK1mutants is complemented by parkin. Nature 441,1157-1161.

Poole, A. C., Thomas, R. E., Andrews, L. A., McBride, H.M., Whitworth, A. J. and Pallanck, L. (2008). ThePINK1/Parkin pathway regulates mitochondrialmorphology. Proc. Natl. Acad. Sci. USA 105, 1638-1643.

Ramirez, A., Heimbach, A., Grundemann, J., Stiller, B.,Hampshire, D., Cid, L. P., Goebel, I., Mubaidin, A. F.,Wriekat, A. L., Roeper, J. et al. (2006). Hereditaryparkinsonism with dementia is caused by mutations inATP13A2, encoding a lysosomal type 5 P-type ATPase.Nat. Genet. 38, 1184-1191.

Sakaguchi-Nakashima, A., Meir, J. Y., Jin, Y.,Matsumoto, K. and Hisamoto, N. (2007). LRK-1, a C.elegans PARK8-related kinase, regulates axonal-dendritic polarity of SV proteins. Curr. Biol. 7, 592-598.

Sawin, E. R., Ranganathan, R. and Horvitz, H. R. (2000).C. elegans locomotory rate is modulated by theenvironment through a dopaminergic pathway and byexperience through a serotonergic pathway. Neuron26, 619-631.

Springer, W., Hoppe, T., Schmidt, E. and Baumeister,R. (2005). A Caenorhabditis elegans Parkin mutantwith altered solubility couples alpha-synucleinaggregation to proteotoxic stress. Hum. Mol. Genet.14, 3407-3423.

Tischler, J., Lenher, B. and Fraser, A. G. (2008).Evolutionary plasticity of gene networks. Nat. Genet. 4,390-391.

van Ham, T. J., Thijssen, K. L., Breitling, R., Hofstra, R.M. W., Plasterk, R. H. A. and Nollen, E. A. A. (2008).C. elegans model identifies genetic modifiers of α-synuclein inclusion formation during aging. PLoSGenet. 4, 10000027.

Ved, R., Saha, S., Westlund, B., Perier, C., Burnam, L.,Sluder, A., Hoener, M., Rodrigues, C. M., Alfonso, A.,Steer, C. et al. (2005). Similar patterns, of,mitochondrial vulnerability and rescue induced bygenetic modification of alpha-synuclein parkin and DJ-1 in Caenorhabditis elegans. J. Biol. Chem. 280, 42655-42668.

West, A. B., Moore, D. J., Choi, C., Andrabi, S. A., Li,X., Dikeman, D., Biskup, S., Zhang, Z., Lim, K. L.,Dawson, V. L. and Dawson, T. M. (2007).Parkinson’s disease-associated mutations inLRRK2 link enhanced GTP-binding and kinaseactivities to neuronal toxicity. Hum. Mol. Genet. 16,223-232.

Wolozin, B., Saha, S., Guillily, M., Ferree, A. and Riley,M. (2008). Investigating convergent actions of geneslinked to familial Parkinson’s disease. Neurodegener Dis.5, 182-185.

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