Neuron Dysfunction Is Induced by Prion Protein with an Insertional Mutation via a Fyn Kinase and Reversed by Sirtuin Activation inCaenorhabditis elegans

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 PKresistant 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.

Translocation of cellular prion protein to non-lipid rafts protects human prion-mediated neuronal damage

“…PrPC/caveolin-1/Fyn signaling is known to be responsible for prion-mediated neurotoxicity (29,30). Some reports showed that inhibition of Fyn kinase activation in PrPC knock-out cells was blocked by PrP(106-126)-induced PrPC/caveolin-1/Fyn signaling and prevented PrPSc-mediated neuronal cell death (19,30).…”

Prion protein inCaenorhabditis elegans

“…32 If ectopic BAX expression is able to induce cell of wild-type PrP in mechanosensory neurons did not result in abnormal behavior. 25 These low expressers, cgIs54 and cgIs55, grew and developed normally (data not shown). However, the high expresser lines, cgIs51, cgIs52 and cgIs53, grew significantly slower than non-transgenic and cgIs54, cgIs55 worms.…”

“…[22][23][24] Very recently, C. elegans as another non-vertebrate model was also reported showing that expression of an insertional mutation of PrP in mechanosensory neurons resulted in a progressive loss of response to touch. 25 In this study, we describe our effort to characterize transgenic C. elegans that broadly express the mouse PrP in whole neurons as well as selectively in dopamine neurons. These established C. elegans prion models mimic some functional and pathogenic characteristics found in mammals, which might facilitate the identification and characterization of molecules as well as pathways that are involved in prion-associated neuropathogenesis.…”

Sirtuin functions in the brain: From physiological to pathological aspects

“…In EAE, a model for multiple sclerosis (MS), overexpression of Sirt1 improves clinical symptoms with less axonal injury [127] . Sirt1 may also protect against neurodegeneration in both nematode and in vitro models of prion toxicity [128][129][130] .…”