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.

Sugimoto A et al. (1994) EMBO J "Baculovirus p35 prevents developmentally programmed cell death and rescues a ced-9 mutant in the nematode Caenorhabditis elegans."

Friesen PD, Rothman JH, Sugimoto A

[EMBO J, 1994]

Programmed cell death, or apoptosis, occurs throughout the course of normal development in most animals and can also be elicited by a number of stimuli such as growth factor deprivation and viral infection. Certain morphological and biochemical characteristics of programmed cell death are similar among different tissues and species. During development of the nematode Caenorhabditis elegans, a single genetic pathway promotes the death of selected cells in a lineally fixed pattern. This pathway appears to be conserved among animal species. The baculovirus p35-encoding gene (p35) is an inhibitor of virus-induced apoptosis in insect cells. Here we demonstrate that expression of p35 in C. elegans prevents death of cells normally programmed to die. This suppression of developmentally programmed cell death results in appearance of extra surviving cells. Expression of p35 can rescue the embryonic lethality of a mutation in ced-9, an endogenous gene homologous to the mammalian apoptotic suppressor bcl-2, whose absence leads to ectopic cell deaths. These results support the hypothesis that viral infection can activate the same cell death pathway as is used during normal development and suggest that baculovirus p35 may act downstream or independently of ced-9 in this pathway.

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.

Sugimoto A et al. (1993) International C. elegans Meeting "Baculovirus p35 inhibits programmed cell death in C. elegans."

Rothman JH, Sugimoto A, Friesen PD

[International C. elegans Meeting, 1993]

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.

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.