ArticlePLoS biology2014
The Wnt receptor Ryk reduces neuronal and cell survival capacity by repressing FOXO activity during the early phases of mutant huntingtin pathogenicity.
Article in PLoS biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04826692 ("Randomized, Double-blind, Placebo-controlled Study to Assess the Effect of Metformin, an Activator of AMPK, on Cognitive Measures of Progression in Huntington's Disease Patients"), which is not on this map. Cited by 29 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
"Randomized, Double-blind, Placebo-controlled Study to Assess the Effect of Metformin, an Activator of AMPK, on Cognitive Measures of Progression in Huntington's Disease Patients"
Who cites it
29 citing papers in PubMed, 44 citations in OpenAlex.
- SIR-2.3/SIRT4 loss enhances proteostasis and neuronal resilience via AMPK-induced autophagy in Huntington's disease models.Cell communication and signaling : CCS · 2026Article
- Identification of Modulators of theAntioxidants (Basel, Switzerland) · 2022Article
- Exploring the Pharmacological Potential of Metformin for Neurodegenerative Diseases.Frontiers in aging neuroscience · 2022Review
- Proteolytic Cleavage of Receptor Tyrosine Kinases.Biomolecules · 2021Review
- Article
- FOXO3 targets are reprogrammed as Huntington's disease neural cells and striatal neurons face senescence with p16Aging cell · 2020Article
- Synergistic activation of AMPK prevents from polyglutamine-induced toxicity in Caenorhabditis elegans.Pharmacological research · 2020Article
- RYK-mediated filopodial pathfinding facilitates midgut elongation.Development (Cambridge, England) · 2020Article
- Treadmill exercise promotes neurogenesis and myelin repair via upregulating Wnt/β‑catenin signaling pathways in the juvenile brain following focal cerebral ischemia/reperfusion.International journal of molecular medicine · 2020Article
- Genetic cooperativity in multi-layer networks implicates cell survival and senescence in the striatum of Huntington's disease mice synchronous to symptoms.Bioinformatics (Oxford, England) · 2020Article
- Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation.Cell death and differentiation · 2019Article
- BMP- and neuropilin 1-mediated motor axon navigation relies on spastin alternative translation.Development (Cambridge, England) · 2018Article
- Oxidative Stress Induces an Interactive Decline in Wnt and Nrf2 Signaling in Degenerating Retinal Pigment Epithelium.Antioxidants & redox signaling · 2018Article
- Neuroprotective and regenerative roles of intranasal Wnt-3a administration after focal ischemic stroke in mice.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2018Article
- Loss of the Spinocerebellar Ataxia type 3 disease protein ATXN3 alters transcription of multiple signal transduction pathways.PloS one · 2018Article
- Keeping Neurons Young and Foxy: FoxOs Promote Neuronal Plasticity.Trends in genetics : TIG · 2018Review
- Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology.Journal of Alzheimer's disease : JAD · 2018Review
- The age factor in axonal repair after spinal cord injury: A focus on neuron-intrinsic mechanisms.Neuroscience letters · 2017Review
- The stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington's disease.Scientific reports · 2017Article
- A new Caenorhabditis elegans model of human huntingtin 513 aggregation and toxicity in body wall muscles.PloS one · 2017Article
Corrections and comments
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Authors and funding
23 authors at 12 institutions in 3 countries.
Funding
Abstract
The Wnt receptor Ryk is an evolutionary-conserved protein important during neuronal differentiation through several mechanisms, including γ-secretase cleavage and nuclear translocation of its intracellular domain (Ryk-ICD). Although the Wnt pathway may be neuroprotective, the role of Ryk in neurodegenerative disease remains unknown. We found that Ryk is up-regulated in neurons expressing mutant huntingtin (HTT) in several models of Huntington's disease (HD). Further investigation in Caenorhabditis elegans and mouse striatal cell models of HD provided a model in which the early-stage increase of Ryk promotes neuronal dysfunction by repressing the neuroprotective activity of the longevity-promoting factor FOXO through a noncanonical mechanism that implicates the Ryk-ICD fragment and its binding to the FOXO co-factor β-catenin. The Ryk-ICD fragment suppressed neuroprotection by lin-18/Ryk loss-of-function in expanded-polyQ nematodes, repressed FOXO transcriptional activity, and abolished β-catenin protection of mutant htt striatal cells against cell death vulnerability. Additionally, Ryk-ICD was increased in the nucleus of mutant htt cells, and reducing γ-secretase PS1 levels compensated for the cytotoxicity of full-length Ryk in these cells. These findings reveal that the Ryk-ICD pathway may impair FOXO protective activity in mutant polyglutamine neurons, suggesting that neurons are unable to efficiently maintain function and resist disease from the earliest phases of the pathogenic process in HD.
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