Caenorhabditis elegans

Caenorhabditis elegans

The roundworm Caenorhabditis elegans represents a valuable animal model system to study Parkinson’s disease (PD) due to the high conservation of genetic and molecular pathways from invertebrates to mammalians, short generation time, short life span of 2-3 weeks, high progeny output and the well-defined morphology of 959 somatic cells, including 302 neuronal cells, their synaptic connections and eight bilaterally-arranged dopaminergic (DA) neurons. High-throughput screens utilizing genetic, RNAi and chemical modifiers can be employed in C. elegans to mitigate the selective loss of DA cells that underlie neurodegeneration in PD¹. Environmental insults and drug compounds that increase the production of reactive oxygen species (ROS) has been shown to induce DA degeneration in several animal models, including the roundworm. Though there is no homolog in C. elegans for alpha-synuclein, the molecular mechanisms of PD pathology can be nevertheless be studied in C. elegans genetic modifier screens since the cellular pathways induced by protein folding stress and aggregation are strongly conserved between invertebrates and mammalians. These studies strongly indicate that C. elegans represents a capable disease model for the identification of new genetic pathway components and pharmacological targets that can potentially ameliorate PD-related neurodegeneration.

Research Highlights:

• The DA D2 receptor agonists, bromocriptine and quinpirole, are neuroprotective against 6-hydroxydopamine (6-OHDA) treatment²
• Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), or its active metabolite MPP⁺, results in reduced mobility and this is correlated with the specific degeneration of DA neurons.  This phenotype is ameliorated by the application of commonly used PD drugs, including the dopamine receptor agonists lisuride and apomorphine, the dopamine transporter inhibitor nomifensine, the protein kinase C inhibitor rottlerin, the nACh receptor antagonist nicotine and the MAO-B inhibitor selegiline³
• In deletion mutants of lrk-1, the homolog of the human leucine-rich repeat kinase LRRK2, synaptic vesicle proteins are aberrantly localized to both presynaptic and dendritic endings in neurons⁴
• LRRK2 overexpression strongly protects against toxicity of the mitochondrial complex I inhibitor rotenone, while lrk-1 knockdown potentiated rotenone toxicity, suggesting that LRKK2 modulates mitochondrial vulnerability⁵
• Transgenic lines that express human wild-type or the mutant A53T alpha-synuclein, delete the E3 ubiquitin ligase parkin, or knock-down the chaperone/protease DJ-1 were more vulnerable than non-transgenics to mitochondrial complex I inhibitors including rotenone, fenperoximate, pyridaben, or stigmatellin and are partially rescued by the antioxidant probucol, the mitochondrial complex II activator, D-beta-hydroxybutyrate, or the anti-apoptotic bile acid tauroursodeoxycholic acid⁶
• Loss of DA neurons and motor deficits were observed in transgenic worms expressing both wild-type and A53T forms of human alpha-synuclein⁷
• Cathepsin D deficiency was shown to exacerbate alpha-synuclein accumulation, while cathepsin D overexpression is protective against the alpha-synuclein-induced DA neurodegeneration⁸
• A whole genome microarray analysis on transgenics expressing human a-synuclein identified the up-regulation of genes involved in mitochondrial function, the proteasomal pathway, lysomal function, embryonic development, reproduction and regulation of growth and the down-regulation of genes involved in nucleosome assembly⁹
• An RNAi genetic modifier screen identified five candidate genes that, when overexpressed, protects DA neurons from alpha-synuclein-induced degeneration¹⁰
• A genome-wide RNAi screen identified 80 genes that, when knocked down, resulted in a premature increase in the number of alpha-synuclein inclusions. These genes include quality control and vesicle-trafficking genes expressed in the ER/Golgi complex and vesicular compartments, and several molecular regulators of lifespan¹¹

 

References:

1              Schmidt E, Seifert M, Baumeister R. Caenorhabditis elegans as a model system for Parkinson's disease. Neurodegener Dis. 2007;4(2-3):199-217. {Abstract}

2              Marvanova M, Nichols CD. Identification of neuroprotective compounds of caenorhabditis elegans dopaminergic neurons against 6-OHDA.  Mol Neurosci. 2007;31(2):127-37. {Abstract}

3              Braungart E, Gerlach M, Riederer P, Baumeister R, Hoener MC. Caenorhabditis elegans MPP+ model of Parkinson's disease for high-throughput drug screenings. Neurodegener Dis. 2004;1(4-5):175-83. {Abstract}

4              Sakaguchi-Nakashima A, Meir JY, Jin Y, Matsumoto K, Hisamoto N. LRK-1, a C. elegans PARK8-related kinase, regulates axonal-dendritic polarity of SV proteins. Curr Biol. 2007 Apr 3;17(7):592-8. {Abstract}

5              Wolozin B, Saha S, Guillily M, Ferree A, Riley M. Investigating convergent actions of genes linked to familial Parkinson's disease. Neurodegener Dis. 2008;5(3-4):182-5. {Abstract}

6              Ved R, Saha S, Westlund B, Perier C, Burnam L, Sluder A, Hoener M, Rodrigues CM, Alfonso A, Steer C, Liu L, Przedborski S, Wolozin B. 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 Dec 30;280(52):42655-68. {Abstract}

7              Lakso M, Vartiainen S, Moilanen AM, Sirviö J, Thomas JH, Nass R, Blakely RD, Wong G. Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans overexpressing human alpha-synuclein. J Neurochem. 2003 Jul;86(1):165-72. {Abstract}

8              Qiao L, Hamamichi S, Caldwell KA, Caldwell GA, Yacoubian TA, Wilson S, Xie ZL, Speake LD, Parks R, Crabtree D, Liang Q, Crimmins S, Schneider L, Uchiyama Y, Iwatsubo T, Zhou Y, Peng L, Lu Y, Standaert DG, Walls KC, Shacka JJ, Roth KA, Zhang J. Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity. Mol Brain. 2008 Nov 21;1(1):17. {Abstract}

9              Vartiainen S, Pehkonen P, Lakso M, Nass R, Wong G. Identification of gene expression changes in transgenic C. elegans overexpressing human alpha-synuclein. Neurobiol Dis. 2006 Jun;22(3):477-86. {Abstract}

10            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 U S A. 2008 Jan 15;105(2):728-33. {Abstract}

11            van Ham TJ, Thijssen KL, Breitling R, Hofstra RM, Plasterk RH, Nollen EA. C. elegans model identifies genetic modifiers of alpha-synuclein inclusion formation during aging. PLoS Genet. 2008 Mar 21;4(3):e1000027. {Abstract}