LAUSR

&NA; Prion diseases are a group of infectious neurodegenerative diseases characterized by multiple neuropathological hallmarks, including accumulation of PrPSc, synaptic damage, and neuronal death. We previously reported that the repressor element 1‐silencing transcription factor (REST), a novel neuroprotective marker in neurodegeneration, protects neurons against neurotoxic peptide (PrP106‐126)‐induced neurotoxicity, but fails to maintain survival following prolonged exposure to PrP106‐126. Because Wnt signaling partially induces REST and is activated by lithium, we investigated the effects of lithium on REST in prion diseases. Lithium restores nuclear expression of REST, which is essential for regulating survival proteins. Lithium also mimics neuroprotective functions when REST is blocked, and these beneficial effects are additive with REST overexpression under physiological conditions. Reciprocally, under PrP106‐126‐stimulated pathological conditions, REST plays a critical role in the neuroprotective mechanisms of lithium treatment. Although lithium recovers Wnt signaling by inhibiting glycogen synthase kinase‐3&bgr; and stabilizing &bgr;‐catenin, restores survival associated proteins after exposure to PrP106‐126 in primary cortical neurons. Knockdown of REST significantly suppresses the neuroprotective function of lithium. Conversely, overexpression of REST partially recovers its actions. Notably, lithium directly alleviates PrP106‐126‐induced synaptic damage and neuronal cell death by preventing changes in presynaptic and postsynaptic marker proteins and promoting survival pathways also partially via the expression of REST. Our results suggest that REST acts as a novel and important nuclear target for lithium. We hypothesize that PrP106‐126‐stimulated neurotoxicity induces Wnt signaling dysfunction and lithium mimics this signaling cascade, suggesting that lithium should be considered as a potential therapeutic agent against prion diseases. Graphical abstract Schematic signaling pathways for lithium acts as a neuroprotective reagent in PrP106‐126‐stimulated primary neurons. Mito, mitochondria. Symbol, phosphorylation. →: Direct stimulatory modification, Symbol: Direct inhibitory modification. Symbol. No caption available. Symbol. No caption available. Figure. No caption available. HighlightsREST acts as a novel neuroprotective nuclear target for lithium.Lithium mimics neuroprotective functions when REST is blocked.Lithium protects primary neurons from PrP106‐126‐induced synaptic damage partially via REST.Lithium protects against PrP106‐126‐induced neurotoxicity partially via REST.