Wang, Y.A. et al. (2017) International Worm Meeting "Microarray profiling of gene expression in Alpha-Synuclein aggregations and its alteration by natural genetic variation in Caenorhabditis elegans ."

Andersen, E.C., Snoek, B.L., Tanny, R.E., Riksen, J.A.G., Sterken, M.G., Kammenga, J.E., Cook, D.E., Harvey, S.C., Wang, Y.A.

[International Worm Meeting, 2017]

Neurodegenerative diseases (NGDs), such as Alzheimer's diseases (AD) and Parkinson's diseases (PD), are characterized by progressive degeneration in the human nervous system. The nematode C. elegans is an excellent model in which to study NGDs due to the high level of conservation of gene functions compared to humans. However, C. elegans research largely relies on a single worm genotype - the canonical N2 strain - limiting the ability to explore how naturally varying alleles alter pathological mechanisms in NGDs. In order to identify how genetic variation acts on NGDs, we analyzed transgenic animals that express aggregating human proteins associated with molecular pathogenic progression of NGDs in five genetic backgrounds. Here, starting with the original transgenic strain expressing the human synaptic protein alpha-synuclein in an N2 genetic background, we have introgressed the PD transgene pkIs2386 [unc-54p::alphasynuclein::YFP + unc-119(+)] into four different wild type genetic backgrounds. Analysis of these new transgenic introgressed lines indicates that transgene effects vary greatly depending on the genetic background. To understand the genetic bases of these phenotypic differences, we have sequenced these new lines to recognize confounder of the heterogeneity in transgenes, measured various aspects of the life history, and investigated gene expression differences by microarray. These analyses identified genes that are up- and down-regulated in all genotypes and genes that expressed at a specific stage to particular genetic backgrounds. For example, the differential developments of those lines have been also confirmed from microarray data that the gene vit-1 expressed at different levels between the lines. Functional enrichment links these genes to the aggregation of alpha-synuclein, which is causative of PD, to the associated developmental arrest, metabolic, and cellular repair mechanisms. Our studies provide opportunities to observe alterations in traits, including global gene expression, associated with the toxicity of misfolded protein aggregation that could not be readily observed in the canonical N2 background. This is a necessary and important step to identify the alleles responsible for individual variation in the onset and progression of NGDs.

Wang YA et al. (2017) Hum Genomics "Genetic variation in neurodegenerative diseases and its accessibility in the model organism Caenorhabditis elegans."

Harvey SC, Wang YA, Kammenga JE

[Hum Genomics, 2017]

BACKGROUND: Neurodegenerative diseases (NGDs) such as Alzheimer's and Parkinson's are debilitating and largely untreatable conditions strongly linked to age. The clinical, neuropathological, and genetic components of NGDs indicate that neurodegeneration is a complex trait determined by multiple genes and by the environment. MAIN BODY: The symptoms of NGDs differ among individuals due totheir genetic background, and this variation affects the onset and progression of NGD and NGD-like states. Such genetic variation affects the molecular and cellular processes underlying NGDs, leading to differential clinical phenotypes. So far, we have a limited understanding of the mechanisms of individual background variation. Here, we consider how variation between genetic backgrounds affects the mechanisms of aging and proteostasis in NGD phenotypes. We discuss how the nematode Caenorhabditis elegans can be used to identify the role of variation between genetic backgrounds. Additionally, we review advances in C. elegans methods that can facilitate the identification of NGD regulators and/or networks. CONCLUSION: Genetic variation both in disease genes and in regulatory factors that modulate onset and progression of NGDs are incompletely understood. The nematode C. elegans represents avaluable system in which to address such questions.

Wang YA et al. (2019) BMC Genomics "Genetic background modifies phenotypic and transcriptional responses in a C. elegans model of -synuclein toxicity."

Wang YA, Harvey SC, Stastna JJ, Riksen JAG, Kammenga JE, Sterken MG, Snoek BL

[BMC Genomics, 2019]

BACKGROUND: Accumulation of protein aggregates are a major hallmark of progressive neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Transgenic Caenorhabditis elegans nematodes expressing the human synaptic protein -synuclein in body wall muscle show inclusions of aggregated protein, which affects similar genetic pathways as in humans. It is not however known how the effects of -synuclein expression in C. elegans differs among genetic backgrounds. Here, we compared gene expression patterns and investigated the phenotypic consequences of transgenic -synuclein expression in five different C. elegans genetic backgrounds. RESULTS: Transcriptome analysis indicates that -synuclein expression effects pathways associated with nutrient storage, lipid transportation and ion exchange and that effects vary depending on the genetic background. These gene expression changes predict that a range of phenotypes will be affected by -synuclein expression. We confirm this, showing that -synuclein expression delayed development, reduced lifespan, increased rate of matricidal hatching, and slows pharyngeal pumping. Critically, these phenotypic effects depend on the genetic background and coincide with the core changes in gene expression. CONCLUSIONS: Together, our results show genotype-specific effects and core alterations in both gene expression and in phenotype in response to -synuclein expression. We conclude that the effects of -synuclein expression are substantially modified by the genetic background, illustrating that genetic background needs to be considered in C. elegans models of neurodegenerative disease.

Wang YA et al. (2020) Genes (Basel) "Genetic Variation in Complex Traits in Transgenic -Synuclein Strains of Caenorhabditis elegans."

van Sluijs L, Harvey SC, Kammenga JE, Sterken MG, Wang YA, Nie Y

[Genes (Basel), 2020]

Different genetic backgrounds can modify the effect of mutated genes. Human -synuclein (<i>SNCA</i>) gene encodes -synuclein, and its oligomeric complexes accumulate with age and mediate the disruption of cellular homeostasis, resulting in the neuronal death that is characteristic of Parkinson's Disease. Polymorphic variants modulate this complex pathologic mechanism. Previously, we constructed five transgenic introgression lines of a <i>Caenorhabditis elegans</i> model of -synuclein using genetic backgrounds that are genetically diverse from the canonical wild-type Bristol N2. A gene expression analysis revealed that the -synuclein transgene differentially affects genome-wide transcription due to background modifiers. To further investigate how complex traits are affected in these transgenic lines, we measured the -synuclein transgene expression, the overall accumulation of the fusion protein of -synuclein and yellow fluorescent protein (YFP), the lysosome-related organelles, and the body size. By using quantitative PCR (qPCR), we demonstrated stable and similar expression levels of the -synuclein transgene in different genetic backgrounds. Strikingly, we observed that the levels of the a-synuclein:YFP fusion protein vary in different genetic backgrounds by using the COPAS biosorter. The quantification of the Nile Red staining assay demonstrates that -synuclein also affects lysosome-related organelles and body size. Our results show that the same -synuclein introgression in different <i>C. elegans</i> backgrounds can produces differing effects on complex traits due to background modifiers.

Infarinato N (2019) J Cell Biol "Xiaochen Wang: Building up our understanding of breaking down."

Infarinato N

[J Cell Biol, 2019]

Wang studies lysosomal degradation pathways using <i>C. elegans</i> as a model system.

Wang JT et al. (2014) Curr Biol "P granules."

Seydoux G, Wang JT

[Curr Biol, 2014]

Wang and Seydoux discuss the functional importance of P granules - the germline-specific RNA granules of C. elegans.

Munro E (2017) Dev Cell "Protein Clustering Shapes Polarity Protein Gradients."

Munro E

[Dev Cell, 2017]

In this issue of Developmental Cell, Dickinson etal. (2017) and Rodriguez etal. (2017), along with Wang etal. (2017) in Nature Cell Biology, show how PAR protein oligomerization can dynamically couple protein diffusion and transport by cortical flow to control kinase activity gradients and polarity in the C.elegans zygote.

Rashid S et al. (2017) Dev Cell "Packing on the Pounds in Response to Bacterial Growth Conditions."

Rashid S, MacNeil LT

[Dev Cell, 2017]

Reporting in Nature Cell Biology, Lin and Wang (2017) show that bacterial methyl metabolism impacts host mitochondrial dynamics and lipid storage in C.elegans. The authors propose a model whereby bacterial metabolic products regulate a nuclear hormone receptor that promotes lipid accumulation through expression of a secreted Hedgehog-like protein.

Vincenz L et al. (2014) Cell "Sugarcoating ER Stress."

Vincenz L, Hartl FU

[Cell, 2014]

The hexosamine biosynthetic pathway (HBP) generates metabolites for protein N- and O-glycosylation. Wang et al. and Denzel et al. report a hitherto unknown link between the HBP and stress in the endoplasmic reticulum. These studies establish the HBP as a critical component of the cellular machinery of protein homeostasis.

Sural S (2023) Trends Genet "Protecting axons in grandchildren."

Sural S

[Trends Genet, 2023]

Prenatal exposure to environmental agents can influence the fitness of not only the fetus, but also subsequent generations. In a recent study, Wang et al. demonstrated that feeding ursolic acid (UA), a plant-derived compound, to Caenorhabditis elegans mothers during their reproductive period prevented neurodegeneration in not only their offspring, but also the F2 progeny.