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.

Dhungel N et al. (2015) Neuron "Parkinson's disease genes VPS35 and EIF4G1 interact genetically and converge on -synuclein."

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.

Buttner S et al. (2014) Cell Cycle "Spermidine protects against -synuclein neurotoxicity."

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.

Gitler AD et al. (2009) Nat Genet "Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity."

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.

Johnson WM et al. Ther Targets Neurol Dis "The roles of redox enzymes in Parkinson's disease: Focus on glutaredoxin."

Mieyal JJ, Wilson-Delfosse AL, Chen SG, Johnson WM

[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.

Wang X et al. (2010) Zhongguo Zhong Yao Za Zhi "[Study of molecular mechanism of anti-Parkinson's disease traditional Chinese medicine using model of Caenorhabditis elegans]"

Gao H, Wang D, Wang X

[Zhongguo Zhong Yao Za Zhi, 2010]

Parkinson's disease (PD) is a neurodegenerative disorder with a complex, multifactorial aetiology. The brains of patients affected with PD are characterized by a loss of neurons in dopamine neurons in the substantia nigra, decreasing of dopamine secretion, and the deposition of Lewy bodies (LBs) in the cytoplasm of remaining neurons. In China the data show that the incidence of Parkinson's disease increases at least 20 times in recent 20 years, and it makes things worse for the aging society. Developing good anti-PD drugs to improve the patient's quality of life is particularly important. The treatment of PD using traditional Chinese medicine (TCM) has made remarkable effect, while the the molecular mechanisms of it is still not known, while elucidating the molecular mechanism of TCM is the base of better understanding its function. Using genetically modified PD model of Caenorhabditis elegans, which is suitable for molecular mechanism study, to explore the interference mechanism of TCM to PD might be an effective way. This review briefly introduces the research progress on molecular mechanism of PD, and then discusses the idea of using C. elegans to study molecular mechanism of TCM intervention to PD.

Sun Q et al. (2020) Anal Chem "Ultrafast Detection of Peroxynitrite in Parkinson's Disease Models Using a Near-Infrared Fluorescent Probe."

Ji CL, Xu J, Zhang CW, Liu Z, Shaibani MSS, Sun Q, Li L, Li Z, Lim K

[Anal Chem, 2020]

Parkinson's disease (PD) is a neurodegenerative disease that devastatingly affects people's lives. Numerous researches have shown that peroxynitrite (ONOO-) plays a pivotal role in the pathogenesis of PD. However, a suitable tool that could quickly and sensitively detect ONOO- in various PD models is still lacking. To this end, we designed and synthesized a series of near-infrared probes that could ultrafast and highly selectively detect ONOO- within seconds by near-infrared fluorescent imaging. Noteworthy, one of those developed probes, NIR-PN1, showed excellent sensing performance and blood-brain-barrier penetrating ability. NIR-PN1 was successfully applied for imaging of ONOO- fluxes in multiple PD models including PC12 cells, Drosophila, C. elegans, and mouse brain, indicating its great potential application not only for understanding the biological roles of ONOO- played in PD but also for early PD diagnosis and treatment.