Wes PD et al. (2001) Nature "C. elegans odour discrimination requires asymmetric diversity in olfactory neurons."

Bargmann CI, Wes PD

[Nature, 2001]

Caenorhabditis elegans senses at least five attractive odours with a single pair of olfactory neurons, AWC, but can distinguish among these odours in behavioural assays(1). The two AWC neurons are structurally and functionally similar, but the G-protein-coupled receptor STR-2 is randomly expressed in either the left or the right AWC neuron, never in both(2). Here we describe the isolation of a mutant, ky542, with specific defects in odour discrimination and odour chemotaxis. ky542 is an allele of nsy-1, a neuronal symmetry, or Nsy, mutant in which STR-2 is expressed in both AWC neurons(2). Other Nsy mutants exhibit discrimination and olfactory defects like those of nsy-1 mutants. Laser ablation of the AWC neuron that does not express STR-2 (AWC(OFF)) recapitulates the behavioural phenotype of Nsy mutants, whereas laser ablation of the STR-2-expressing AWC neuron (AWC(ON)) causes different chemotaxis defects. We propose that odour discrimination can be achieved by segregating the detection of different odours into distinct olfactory neurons or into unique combinations of olfactory neurons.

PD Wes et al. (1999) International C. elegans Meeting "Information Coding in the C. elegans Olfactory System"

PD Wes, CI Bargmann

[International C. elegans Meeting, 1999]

Different signal transduction pathways coexist within the same cell, interacting in complex ways to produce novel responses, yet preserving fidelity. The olfactory system of C. elegans can be used to study the molecular basis of information processing within a single cell. C. elegans senses a broad array of attractive odors with just two pairs of sensory neurons, AWA and AWC. A number of odorants activate each neuron. Isoamyl alcohol (iaa), 2,3-pentanedione (pd), butanone (bt) and benzaldehyde (bz) all activate AWC, and, furthermore, each odorant utilizes the same cGMP signaling cascade. Nevertheless, animals are able to distinguish amongst some of these odorants. For instance, when placed in a uniform field of bt, animals will no longer chemotax toward a point source of bt (defined as saturation), yet will chemotax toward bz. A screen was conducted to identify mutants that responded normally to bz in the absence of bt, but failed to chemotax toward a point source of bz in a field of bt (defined as cross-saturation). 20,000 haploid genomes were screened, yielding 25 candidates. A range of phenotypes was observed, with the strongest mutant, ky542 , displaying total cross-saturation of bz by bt. ky542 exhibits other defects in odor recognition or processing. It has reduced sensitivity to pd, though its sensitivity to all others odorants remains undiminished. ky542 also has enhanced discrimination between iaa and bz. Olfactory discrimination is also enhanced by starvation, a form of plasticity modulated by serotonin 1 . In addition, ky542 and other cross-saturation mutants display a defect in olfactory adaptation, a long-lasting form of signal desensitization (see abstract by Noelle l'Etoile and C.B.). Several models that may shed light on these olfactory phenotypes are being tested. Understanding the principles behind olfactory discrimination may provide new insights into information coding within single cells, and may also elucidate some forms of behavioral plasticity that are modulated by C. elegans olfaction. 1 Colbert, H.A., Bargmann, C.I. 1997.

Jansen IE et al. (2017) Genome Biol "Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing."

Lubbe SJ, Gibbs JR, Ye H, Li Y, Nalls MA, Ryten M, Nollen EA, Jansen IE, Simon-Sanchez J, Michels H, Majounie E, Singleton AB, Drouet V, Lechler MC, Shulman JM, Heetveld S, Chouhan AK, Brice A, Amin N, Jain S, van Duijn CM, Yogi P, Rizzu P, Lesage S, Morris HR, Vandrovcova J, Heutink P, Blauwendraat C, David DC, Castillo-Lizardo M, Botia JA, Seinstra RI

[Genome Biol, 2017]

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced -synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies.

Plasterk RHA et al. (2000) West Coast Worm Meeting "Information Coding in the C. elegans Olfactory System"

Plasterk RHA, Bargmann CI, Sagasti A, Wes PD

[West Coast Worm Meeting, 2000]

In order to better understand the molecular and cellular basis of behavior, we have begun to genetically scrutinize odorant discrimination in C. elegans. C. elegans senses a broad array of attractive odors with just two pairs of sensory neurons, AWA and AWC. Each member of the pair are thought to be largely identical, except that the G protein-coupled receptor, STR-2, is stochastically expressed in either the left or right AWC neuron. A number of odorants activate each neuron. Isoamyl alcohol (iaa), 2,3-pentanedione (pd), butanone (bu) and benzaldehyde (bz) all activate AWC. Each odorant utilizes the same cGMP signaling cascade, yet animals retain the ability to distinguish amongst some of these odorants. For instance, when placed in a uniform field of bu, animals will no longer chemotax toward a point source of bu (defined as saturation), yet will chemotax toward bz. A screen was conducted to identify mutants that failed to chemotax toward a point source of bz in a field of bu (defined as cross-saturation). One mutant, ky542, displayed total cross-saturation, as well as defects in pd chemotaxis and olfactory adaptation. ky542 was cloned and found to be an allele of nsy-1, a "neuronal symmetry" mutant in which STR-2 is expressed in both AWC neurons. Other nsy mutants, including nsy-2, nsy-3 and egl-2(gf), also showed cross-saturation phenotypes. One model proposes that odorant discrimination is achieved by expressing the bu receptor in the STR-2 "ON" cell, the pd receptor in the STR-2 "OFF", and the bz receptor in both cells. A variety of forward and reverse genetic studies and ablation experiments support this model. Nevertheless, neuronal asymmetry cannot fully account for odorant discrimination since the 2 AWC neurons can distinguish at least 4 classes of odorants. For instance, iaa is distinguished from bu, bz and pd. Therefore, informational processing must also occur intracellularly. Since at least 6 Ga proteins are expressed in AWC, we reasoned that this protein family may provide the requisite degree of diversity for signaling specificity. Indeed, gpa-5 is required for discrimination between iaa and bu in AWC, suggesting that different odorants may employ specific modulatory signaling pathways within single cells.

Perni M et al. (2021) Front Cell Dev Biol "Comparative Studies in the A30P and A53T -Synuclein C. elegans Strains to Investigate the Molecular Origins of Parkinson's Disease."

Chen SW, Xu CK, van Ham TJ, Kirkegaard JB, Cohen SIA, Vendruscolo M, van der Goot A, Kaminski Schierle GS, Knowles TPJ, Seinstra R, Muller MBD, Nollen EAA, Laine RF, Kumita JR, Aprile FA, Perni M, Barbut D, Thijssen K, Kaminski CF, Sormanni P, Dobson CM, Flagmeier P, Ma KY, Limbocker R, Zasloff M, Fusco G, Challa PK, De Simone A, Sinnige T

[Front Cell Dev Biol, 2021]

The aggregation of -synuclein is a hallmark of Parkinson's disease (PD) and a variety of related neurological disorders. A number of mutations in this protein, including A30P and A53T, are associated with familial forms of the disease. Patients carrying the A30P mutation typically exhibit a similar age of onset and symptoms as sporadic PD, while those carrying the A53T mutation generally have an earlier age of onset and an accelerated progression. We report two <i>C. elegans</i> models of PD (PD_A30P and PD_A53T), which express these mutational variants in the muscle cells, and probed their behavior relative to animals expressing the wild-type protein (PD_WT). PD_A30P worms showed a reduced speed of movement and an increased paralysis rate, control worms, but no change in the frequency of body bends. By contrast, in PD_A53T worms both speed and frequency of body bends were significantly decreased, and paralysis rate was increased. -Synuclein was also observed to be less well localized into aggregates in PD_A30P worms compared to PD_A53T and PD_WT worms, and amyloid-like features were evident later in the life of the animals, despite comparable levels of expression of -synuclein. Furthermore, squalamine, a natural product currently in clinical trials for treating symptomatic aspects of PD, was found to reduce significantly the aggregation of -synuclein and its associated toxicity in PD_A53T and PD_WT worms, but had less marked effects in PD_A30P. In addition, using an antibody that targets the N-terminal region of -synuclein, we observed a suppression of toxicity in PD_A30P, PD_A53T and PD_WT worms. These results illustrate the use of these two <i>C. elegans</i> models in fundamental and applied PD research.

Chandler RJ et al. (2021) Biosci Rep "Modelling the Functional Genomics of Parkinson's in Caenorhabditis elegans: LRRK2 and Beyond."

Cogo S, Lewis PA, Kevei E, Chandler RJ

[Biosci Rep, 2021]

For decades, Parkinson's disease (PD) cases have been genetically categorised into familial, when caused by mutations in single genes with a clear inheritance pattern in affected families, or idiopathic, in the absence of an evident monogenic determinant. Recently, genome-wide association studies (GWAS) have revealed how common genetic variability can explain up to 36% of PD heritability and that PD manifestation is often determined by multiple variants at different genetic loci. Thus, one of the current challenges in PD research stands in modelling the complex genetic architecture of this condition and translating this into functional studies. Caenorhabditis elegans provide a profound advantage as a reductionist, economical model for PD research, with a short lifecycle, straightforward genome engineering and high conservation of PD relevant neural, cellular and molecular pathways. Functional models of PD genes utilising C. elegans, show many phenotypes recapitulating pathologies observed in PD. When contrasted with mammalian in vivo and in vitro models, these are frequently validated, suggesting relevance of C. elegans in the development of novel PD functional models. This review will discuss how the nematode C. elegans PD models have contributed to the uncovering of molecular and cellular mechanisms of disease, with a focus on the genes most commonly found as causative in familial PD and risk factors in idiopathic PD. Specifically, we will examine the current knowledge on a central player in both familial and idiopathic PD, Leucine-rich repeat kinase 2 (LRRK2) and how it connects to multiple PD associated GWAS candidates and Mendelian disease-causing genes.

Wu Y et al. (2023) Antioxidants (Basel) "Vitamin B12 Ameliorates the Pathological Phenotypes of Multiple Parkinson's Disease Models by Alleviating Oxidative Stress."

Lim KL, Yang N, Wu Q, Li L, Xu J, Li Z, Xin C, Zhang C, Zhao Z, Ma B, Wu Y, Yu C

[Antioxidants (Basel), 2023]

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the substantia nigra of the midbrain. The etiology of PD has yet to be elucidated, and the disease remains incurable. Increasing evidence suggests that oxidative stress is the key causative factor of PD. Due to their capacity to alleviate oxidative stress, antioxidants hold great potential for the treatment of PD. Vitamins are essential organic substances for maintaining the life of organisms. Vitamin deficiency is implicated in the pathogenesis of various diseases, such as PD. In the present study, we investigated whether administration of vitamin B12 (VB12) could ameliorate PD phenotypes in vitro and in vivo. Our results showed that VB12 significantly reduced the generation of reactive oxygen species (ROS) in the rotenone-induced SH-SY5Y cellular PD model. In a Parkin gene knockout <i>C. elegans</i> PD model, VB12 mitigated motor dysfunction. Moreover, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse PD model, VB12 also displayed protective effects, including the rescue of mitochondrial function, dopaminergic neuron loss, and movement disorder. In summary, our results suggest that vitamin supplementation may be a novel method for the intervention of PD, which is safer and more feasible than chemical drug treatment.

Pu P et al. (2006) Neurosci Bull "C. elegans as a model system for Parkinson disease."

LE WD, Pu P

[Neurosci Bull, 2006]

Parkinson disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra. Although investigation in mammalian animal models of PD has enhanced our understanding of PD, the complexity of the mammalian nervous system and our inability to visualize DA neurons in vivo restricts the advances in elucidating the molecular mechanisms of PD. Conservation between C. elegans and mammals in genomic, biosynthetic and metabolic pathways as well as the advantages of observing DA neurons morphology in vivo and the ease of transgenic and genetic manipulation make C. elegans an excellent model organism for PD.

Lee BD et al. (2012) Trends Pharmacol Sci "Leucine-rich repeat kinase 2 (LRRK2) as a potential therapeutic target in Parkinson's disease."

Dawson VL, Lee BD, Dawson TM

[Trends Pharmacol Sci, 2012]

Parkinson's disease (PD) is caused by the progressive degeneration of dopaminergic neurons in the substantia nigra. Although the etiology for most PD remains elusive, the identification of specific genetic defects in familial cases of PD and the signaling pathways governed by these genes has provided tremendous insight into PD pathogenesis. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are frequently found in familial and sporadic PD. Although current knowledge regarding the regulatory mechanisms of LRRK2 activation is limited, it is becoming increasingly evident that aberrant kinase activity of the pathologic mutants of LRRK2 is associated with neurodegeneration, suggesting that the kinase activity of LRRK2 is a potential therapeutic target. In addition, LRRK2 inhibitors might provide valuable tools to understand the pathophysiological and physiological roles of LRRK2 as well as the etiology of PD. We discuss here the potential and feasibility of targeting LRRK2 as a therapeutic strategy for PD.

Deng H et al. (2014) Ageing Res Rev "Genetic variants and animal models in SNCA and Parkinson disease."

Deng H, Yuan L

[Ageing Res Rev, 2014]

Parkinson disease (PD; MIM 168600) is the second most common progressive neurodegenerative disorder characterized by a variety of motor and non-motor features. To date, at least 20 loci and 15 disease-causing genes for parkinsonism have been identified. Among them, the -synuclein (SNCA) gene was associated with PARK1/PARK4. Point mutations, duplications and triplications in the SNCA gene cause a rare dominant form of PD in familial and sporadic PD cases. The -synuclein protein, a member of the synuclein family, is abundantly expressed in the brain. The protein is the major component of Lewy bodies and Lewy neurites in dopaminergic neurons in PD. Further understanding of its role in the pathogenesis of PD through various genetic techniques and animal models will likely provide new insights into our understanding, therapy and prevention of PD.