Neuron dysfunction is induced by prion protein with an insertional mutation via a Fyn kinase and reversed by sirtuin activation in Caenorhabditis elegans.
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.
Bizat
Nicolas
N
Unit 894, Laboratory of Neuronal Cell Biology and Pathology, Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes, Equipe d'accueil 4059, 75014 Paris, France.
Peyrin
Jean-Michel
JM
Haïk
Stephane
S
Cochois
Véronique
V
Beaudry
Patrick
P
Laplanche
Jean-Louis
JL
Néri
Christian
C
D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal / Q000502:physiology; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D019286:Endopeptidase K / Q000378:metabolism; D006801:Humans; D008465:Mechanoreceptors / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D051379:Mice; D016254:Mutagenesis, Insertional; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D011328:Prions / Q000235:genetics* / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D000077185:Resveratrol; D037761:Sirtuins / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D014110:Touch / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D018696:Neuroprotective Agents; D011328:Prions; D013267:Stilbenes; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases; D019286:Endopeptidase K; C507014:SIR-2.1 protein, C elegans; D037761:Sirtuins; D000077185:Resveratrol
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