Neuron Dysfunction is Induced by Prion Protein with an Insertional Mutation Via a Fyn Kinase and Reversed by Sirtuin Activation Incaenorhabditis 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 identifysrc-2, a Fyn-related kinase, as a gene required for human PrP with an insertional mutation to be neurotoxic inCaenorhabditis elegans,and the longevity modulatorsir-2.1/SIRT1, a sirtuin deacetylase, as a modifier of prion neurotoxicity. The expression of octarepeat-expanded PrP inC. elegansmechanosensory 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) ofsrc-2greatly reduced mutant PrP neurotoxicity without reducing PK-resistant PrP levels. Increasedsir-2.1dosage reversed mutant PrP neurotoxicity, whereassir-2.1LOF 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 asir-2.1-dependent manner. Additionally, resveratrol reversed cell death caused by mutant PrP in cerebellar granule neurons fromprnp-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.