ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2010
Neuron dysfunction is induced by prion protein with an insertional mutation via a Fyn kinase and reversed by sirtuin activation in Caenorhabditis elegans.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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23 citing papers in PubMed, 44 citations in OpenAlex.
- Article
- Article
- Could Sirtuin Activities Modify ALS Onset and Progression?Cellular and molecular neurobiology · 2017Review
- Treatment of SMB-S15 Cells with Resveratrol Efficiently Removes the PrP(Sc) Accumulation In Vitro and Prion Infectivity In Vivo.Molecular neurobiology · 2016Article
- Activation of zebrafish Src family kinases by the prion protein is an amyloid-β-sensitive signal that prevents the endocytosis and degradation of E-cadherin/β-catenin complexes in vivo.Molecular neurodegeneration · 2016Article
- Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression.Molecular neurodegeneration · 2015Article
- The Role of TLR4 and Fyn Interaction on Lipopolysaccharide-Stimulated PAI-1 Expression in Astrocytes.Molecular neurobiology · 2015Article
- Prion degradation pathways: Potential for therapeutic intervention.Molecular and cellular neurosciences · 2015Review
- Scrapie infection in experimental rodents and SMB-S15 cells decreased the brain endogenous levels and activities of Sirt1.Journal of molecular neuroscience : MN · 2015Article
- Using C. elegans to discover therapeutic compounds for ageing-associated neurodegenerative diseases.Chemistry Central journal · 2015Review
- Caenorhabditis elegans dnj-14, the orthologue of the DNAJC5 gene mutated in adult onset neuronal ceroid lipofuscinosis, provides a new platform for neuroprotective drug screening and identifies a SIR-2.1-independent action of resveratrol.Human molecular genetics · 2014Article
- SIRT1 in neurodevelopment and brain senescence.Neuron · 2014Review
- Common themes in PrP signaling: the Src remains the same.Frontiers in cell and developmental biology · 2014Article
- Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein.Neuron · 2013Article
- SIRT1 and SIRT2: emerging targets in neurodegeneration.EMBO molecular medicine · 2013Review
- Polyphenols: multipotent therapeutic agents in neurodegenerative diseases.Oxidative medicine and cellular longevity · 2013Review
- Sirt1: def-eating senescence?Cell cycle (Georgetown, Tex.) · 2012Review
- Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons.Nature neuroscience · 2012Article
- Is tau ready for admission to the prion club?Prion · 2012Review
- Role and Therapeutic Potential of the Pro-Longevity Factor FOXO and Its Regulators in Neurodegenerative Disease.Frontiers in pharmacology · 2012Article
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7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Although prion propagation is well understood, the signaling pathways activated by neurotoxic forms of prion protein (PrP) and those able to mitigate pathological phenotypes remain largely unknown. Here, we identify src-2, a Fyn-related kinase, as a gene required for human PrP with an insertional mutation to be neurotoxic in Caenorhabditis elegans, and the longevity modulator sir-2.1/SIRT1, a sirtuin deacetylase, as a modifier of prion neurotoxicity. The expression of octarepeat-expanded PrP in C. elegans mechanosensory neurons led to a progressive loss of response to touch without causing cell death, whereas wild-type PrP expression did not alter behavior. Transgenic PrP molecules showed expression at the plasma membrane, with protein clusters, partial resistance to proteinase K (PK), and protein insolubility detected for mutant PrP. Loss of function (LOF) of src-2 greatly reduced mutant PrP neurotoxicity without reducing PK-resistant PrP levels. Increased sir-2.1 dosage reversed mutant PrP neurotoxicity, whereas sir-2.1 LOF showed aggravation, and these effects did not alter PK-resistant PrP. Resveratrol, a polyphenol known to act through sirtuins for neuroprotection, reversed mutant PrP neurotoxicity in a sir-2.1-dependent manner. Additionally, resveratrol reversed cell death caused by mutant PrP in cerebellar granule neurons from prnp-null mice. These results suggest that Fyn mediates mutant PrP neurotoxicity in addition to its role in cellular PrP signaling and reveal that sirtuin activation mitigates these neurotoxic effects. Sirtuin activators may thus have therapeutic potential to protect from prion neurotoxicity and its effects on intracellular signaling.
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