The Anti-Apoptotic Activity of β-Synuclein Mediated via Akt Signaling Is Severely Lost During Prion Infection

Prion diseases are fatal neurodegenerative disorders characterized by profound neuronal damage. Despite evidence supporting a neuroprotective role for β-synuclein (β-syn) in neurodegeneration, its potential functions and mechanisms in prion disease have not been elucidated. To investigate the role of β-syn, we systematically analyzed its alterations in the central nervous system of several prion-infected rodent models and cell models. A series of biochemical, cellular, and immunofluorescence assays were conducted to explore the relationship between β-syn and protein kinase B (Akt) signaling and between β-syn and prion protein (PrP), and its neuroprotective role in prion disease. Student's t-test was used for statistics. At the terminal stage of prion disease, β-syn and Akt exhibited a parallel and remarkable decrease in rodent brains, contrasting with the slight but significant increase observed at early to middle stages. Dual-stained immunofluorescence assays confirmed that β-syn is localized within NeuN-positive neurons. Further structural and functional analyses revealed a high-affinity molecular interaction between β-syn and Akt, with the N-terminal region of β-syn being essential for binding to Akt1. In a cell model of PrP aggregation, β-syn overexpression suppressed cytochrome c-induced apoptosis, which was demonstrated by decreased levels of cleaved caspase-3. Notably, this anti-apoptotic effect was partially abolished upon Akt knockdown, indicating a dependence on Akt signaling. Moreover, colocalization of β-syn and PrP was observed in rodent brains. Consistently, in cellular models of prion infection and PrP aggregation, β-syn overexpression not only reduced PrP levels but also ameliorated its aberrant histological distribution. Our findings demonstrate that the anti-apoptotic activity of β-syn, mediated via Akt signaling, is severely lost during prion infection, thereby suggesting a mechanism of intrinsic neuronal vulnerability and revealing a novel therapeutic strategy.