Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans.

Link, Christopher D.

doi:10.1073/pnas.92.20.9368

Cited by 621 publications

(542 citation statements)

References 40 publications

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“…Several transgenic C. elegans lines have been successfully established to study human neurodegenerative disorders (35)(36)(37)(38)(39)(40). Such heterologous genetic models have proven to be very useful for understanding disease pathogenesis and developing therapeutic strategy.…”

Section: Discussionmentioning

confidence: 99%

Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Chen

Huang

Cheng

2011

Proc. Natl. Acad. Sci. U.S.A.

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Defects in neuronal connectivity of the brain are well documented among schizophrenia patients. Although the schizophrenia susceptibility gene Disrupted-in-Schizophrenia 1 (DISC1) has been implicated in various neurodevelopmental processes, its role in regulating axonal connections remains elusive. Here, a heterologous DISC1 transgenic system in the relatively simple and wellcharacterized Caenorhabditis elegans motor neurons has been established to investigate whether DISC1 regulates axon guidance during development. Transgenic DISC1 in C. elegans motor neurons is enriched in the migrating growth cones and causes guidance defects of their growing axons. The abnormal axonal phenotypes induced by DISC1 are similar to those by gain-of-function rac genes. In vivo genetic interaction studies revealed that the UNC-73/TRIO-RAC-PAK signaling pathway is activated by ectopic DISC1 in C. elegans motor axons. Using in vitro GST pull-down and coimmunoprecipitation assays, we found that DISC1 binds specifically to the amino half of spectrin repeats of TRIO, thereby preventing TRIO's amino half of spectrin repeats from interacting with its first guanine nucleotide exchange factor (GEF) domain, GEF1, and facilitating the recruitment of RAC1 to TRIO. In cultured mammalian cells, RAC1 is activated by increased TRIO's GEF activity when DISC1 is present. These results together indicate that the TRIO-RAC-PAK signaling pathway can be exploited and modulated by DISC1 to regulate axonal connectivity in the developing brain.genetic model | rolipram S chizophrenia is a neurodevelopmental disorder with genetic predispositions (1, 2). Although the etiology and neuropathology of schizophrenia are still elusive, functional and neuroanatomical studies from patients have documented various abnormalities in the diseased brain. In particular, defects in neuronal connectivity during development have been proposed as an important precipitating factor for schizophrenia, which is thought to be unmasked by other developmental events or environmental stressors later in life (3). It is therefore likely that some of the major schizophrenia susceptibility genes are important for regulating axonal connections during development.In recent years, the effort to search for genes susceptible to schizophrenia has led to the identification of the Disrupted-inSchizophrenia 1 (DISC1) gene, whose mutation is highly associated with schizophrenia and other major human mental diseases (4). DISC1 has roles in neuron proliferation, neuron migration, axon outgrowth, and synapse formation/maturation (5-8). In our previous studies, we identified an unexpected role of DISC1 in regulating the guidance of developing axons in the adult-born hippocampal dentate granule cells (5, 9). These effects expand the known functions of DISC1 but sheds little light on how DISC1 effects axon guidance.To systemically study the role of DISC1 in axon guidance and to identify the signaling pathways that might be involved, we set out to establish a heterologous genetic system in the nematode Ca...

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Section: Discussionmentioning

confidence: 99%

Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Chen

Huang

Cheng

2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Importantly, the endocytosis-related genes we originally identified in our yeast screen, which are also known AD risk factors in humans, suppress Aβ toxicity in this nematode model (8). Expressing Aβ in glutamatergic neurons enables a quantitative measure of neurodegeneration and differs from previous approaches in the nematode where Aβ expressed within the body wall muscle cells caused a motor phenotype (24,25). As previously described, the percentage of worms with the WT number of neurons decreased from 3 to 7 d post larval hatching [ Fig.…”

Section: Screen For Compounds That Rescue Aβ Toxicity In Yeastmentioning

confidence: 99%

Clioquinol promotes the degradation of metal-dependent amyloid-β (Aβ) oligomers to restore endocytosis and ameliorate Aβ toxicity

Matlack

Tardiff

Narayan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

157

141

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Alzheimer's disease (AD) is a common, progressive neurodegenerative disorder without effective disease-modifying therapies. The accumulation of amyloid-β peptide (Aβ) is associated with AD. However, identifying new compounds that antagonize the underlying cellular pathologies caused by Aβ has been hindered by a lack of cellular models amenable to high-throughput chemical screening. To address this gap, we use a robust and scalable yeast model of Aβ toxicity where the Aβ peptide transits through the secretory and endocytic compartments as it does in neurons. The pathogenic Aβ 1-42 peptide forms more oligomers and is more toxic than Aβ 1-40 and genome-wide genetic screens identified genes that are known risk factors for AD. Here, we report an unbiased screen of ∼140,000 compounds for rescue of Aβ toxicity. Of ∼30 hits, several were 8-hydroxyquinolines (8-OHQs). Clioquinol (CQ), an 8-OHQ previously reported to reduce Aβ burden, restore metal homeostasis, and improve cognition in mouse AD models, was also effective and rescued the toxicity of Aβ secreted from glutamatergic neurons in Caenorhabditis elegans. In yeast, CQ dramatically reduced Aβ peptide levels in a copper-dependent manner by increasing degradation, ultimately restoring endocytic function. This mirrored its effects on copper-dependent oligomer formation in vitro, which was also reversed by CQ. This unbiased screen indicates that copper-dependent Aβ oligomer formation contributes to Aβ toxicity within the secretory/endosomal pathways where it can be targeted with selective metal binding compounds. Establishing the ability of the Aβ yeast model to identify disease-relevant compounds supports its further exploitation as a validated early discovery platform.phenotypic small-molecule screen | metal chelation A lzheimer's disease (AD) is a common and devastating neurodegenerative disorder that is projected to increase in frequency as our population ages. The lack of disease-modifying therapies requires new approaches to address the underlying mechanisms of cellular dysfunction and identify potential therapeutics.The amyloid-β peptide (Aβ) plays a major role in AD and ultimately leads to neuronal death and cognitive impairment (1). Aβ peptides of ∼40 aa are generated by the successive cleavage of the amyloid precursor protein (APP) by β-and γ-secretases. Mutations in APP or γ-secretase cause familial AD and bias APP cleavage toward a 42-aa Aβ peptide that predominates in Aβ plaques, is more aggregation prone, and is toxic to neurons (2, 3). Although Aβ plaques are a common, conspicuous feature of pathology in diseased brains, increasing evidence suggests that small oligomers of Aβ are the most toxic species (4, 5).

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“…In vivo experiments were also performed in order to investigate the protective effect of TTR. In Caenorhabditis elegans expressing human A-Beta (1-42), TTR rescued the neurodegeneration triggered by the toxic peptide [13]. Studies in transgenic mice overexpressing mutant APP revealed slow disease progression and lack of neurodegeneration attributed to TTR expression [7].…”

Section: Introductionmentioning

confidence: 99%

Transthyretin binding to A‐Beta peptide – Impact on A‐Beta fibrillogenesis and toxicity

Costa¹,

Gonçalves²,

Saraiva³

et al. 2008

FEBS Letters

132

145

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It has been suggested that transthyretin (TTR) is involved in preventing A-Beta fibrillization in AlzheimerÕs disease (AD). Here, we characterized the TTR/A-Beta interaction by competition binding assays. TTR binds to different A-Beta peptide species: soluble (Kd, 28 nM), oligomers and fibrils; diverse TTR variants bind differentially to A-Beta. Transmission electron microscopy (TEM) analysis demonstrated that TTR is capable of interfering with A-Beta fibrillization by both inhibiting and disrupting fibril formation. Co-incubation of the two molecules resulted in the abolishment of A-Beta toxicity. Our results confirmed TTR as an A-Beta ligand and indicated the inhibition/disruption of A-Beta fibrils as a possible mechanism underlying the protective role of TTR in AD.

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Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans.

Cited by 621 publications

References 40 publications

Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Clioquinol promotes the degradation of metal-dependent amyloid-β (Aβ) oligomers to restore endocytosis and ameliorate Aβ toxicity

Transthyretin binding to A‐Beta peptide – Impact on A‐Beta fibrillogenesis and toxicity

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