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[
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.
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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.
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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<sub>A30P</sub> and PD<sub>A53T</sub>), which express these mutational variants in the muscle cells, and probed their behavior relative to animals expressing the wild-type protein (PD<sub>WT</sub>). PD<sub>A30P</sub> 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<sub>A53T</sub> 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<sub>A30P</sub> worms compared to PD<sub>A53T</sub> and PD<sub>WT</sub> 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<sub>A53T</sub> and PD<sub>WT</sub> worms, but had less marked effects in PD<sub>A30P</sub>. In addition, using an antibody that targets the N-terminal region of -synuclein, we observed a suppression of toxicity in PD<sub>A30P</sub>, PD<sub>A53T</sub> and PD<sub>WT</sub> worms. These results illustrate the use of these two <i>C. elegans</i> models in fundamental and applied PD research.
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[
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.
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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.
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[
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.
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Gitler AD, Chartron JW, Kosberg K, Eleuteri S, Dhungel N, Spencer B, Frydman J, Masliah E, Adame A, Shen K, Kramer NJ, Fields JA, Lashuel H, Li LB, Stafa K
[
Neuron,
2015]
UNLABELLED: Parkinson's disease (PD) is a common neurodegenerative disorder. Functional interactions between some PD genes, like PINK1 and parkin, have been identified, but whether other ones interact remains elusive. Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. We also show interactions between VPS35, EIF4G1, and -synuclein, a protein with a key role in PD. We extend our findings from yeast to an animal model and show that these interactions are conserved in neurons and in transgenic mice. Our studies reveal unexpected genetic and functional interactions between two seemingly unrelated PD genes and functionally connect them to -synuclein pathobiology in yeast, worms, and mouse. Finally, we provide a resource of candidate PD genes for future interrogation.
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Madeo F, Markaki M, Michael E, Carmona-Gutierrez D, Alavian-Ghavanini A, Habernig L, Tavernarakis N, Broeskamp F, Eisenberg T, Buttner S, Kroemer G, Sommer C, Sigrist SJ
[
Cell Cycle,
2014]
As our society ages, neurodegenerative disorders like Parkinsons disease (PD) are increasing in pandemic proportions. While mechanistic understanding of PD is advancing, a treatment with well tolerable drugs is still elusive. Here, we show that administration of the naturally occurring polyamine spermidine, which declines continuously during aging in various species, alleviates a series of PD-related degenerative processes in the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, two established model systems for PD pathology. In the fruit fly, simple feeding with spermidine inhibited loss of climbing activity and early organismal death upon heterologous expression of human -synuclein, which is thought to be the principal toxic trigger of PD. In this line, administration of spermidine rescued -synuclein-induced loss of dopaminergic neurons, a hallmark of PD, in nematodes. Alleviation of PD-related neurodegeneration by spermidine was accompanied by induction of autophagy, suggesting that this cytoprotective process may be responsible for the beneficial effects of spermidine administration.
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Caldwell GA, Chesi A, Geddie ML, Gitler AD, Strathearn KE, Lindquist S, Rochet JC, Caldwell KA, Cooper AA, Hamamichi S, Hill KJ
[
Nat Genet,
2009]
Parkinson''s disease (PD), dementia with Lewy bodies and multiple system atrophy, collectively referred to as synucleinopathies, are associated with a diverse group of genetic and environmental susceptibilities. The best studied of these is PD. alpha-Synuclein (alpha-syn) has a key role in the pathogenesis of both familial and sporadic PD, but evidence linking it to other predisposition factors is limited. Here we report a strong genetic interaction between alpha-syn and the yeast ortholog of the PD-linked gene ATP13A2 (also known as PARK9). Dopaminergic neuron loss caused by alpha-syn overexpression in animal and neuronal PD models is rescued by coexpression of PARK9. Further, knockdown of the ATP13A2 ortholog in Caenorhabditis elegans enhances alpha-syn misfolding. These data provide a direct functional connection between alpha-syn and another PD susceptibility locus. Manganese exposure is an environmental risk factor linked to PD and PD-like syndromes. We discovered that yeast PARK9 helps to protect cells from manganese toxicity, revealing a connection between PD genetics (alpha-syn and PARK9) and an environmental risk factor (PARK9 and manganese). Finally, we show that additional genes from our yeast screen, with diverse functions, are potent modifiers of alpha-syn-induced neuron loss in animals, establishing a diverse, highly conserved interaction network for alpha-syn.
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[
Ther Targets Neurol Dis
]
Parkinson's disease (PD) results from the loss of dopaminergic neurons in the substantia nigra portion of the midbrain, and represents the second most common neurodegenerative disease in the world. Although the etiology of PD is currently unclear, oxidative stress and redox dysfunction are generally understood to play key roles in PD pathogenesis and progression. Aging and environmental factors predispose cells to adverse effects of redox changes. In addition to these factors, genetic mutations linked to PD have been observed to disrupt the redox balance. Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with autosomal dominant PD, and several of these mutations have also been shown to increase the levels of reactive oxygen species in cells. Anti-oxidant proteins are necessary to restore the redox balance and maintain cell viability. Over the past decade studies have started to demonstrate the critical importance for redox proteins mediating neuronal protection in models of PD. This commentary briefly describes some of the factors hypothesized to contribute to PD, specifically regarding the redox changes that occur in PD. Dysregulation of redox proteins in PD is highlighted by some of the work detailing the roles of peroxiredoxin-3 and thioredoxin-1 in models of PD. In an attempt to generate novel therapies for PD, several potent inhibitors of LRRK2 have been developed. The use of these compounds, both as tools to understand the biology of LRRK2 and as potential therapeutic strategies is also discussed. This mini-review then provides a historical prospective on the discovery and characterization of glutaredoxin (Grx1), and briefly describes current understanding of the role of Grx1 in PD. The review concludes by highlighting our recent publication describing the novel role for Grx1 in mediating dopaminergic neuronal protection both in vitro and in vivo.