A Friend or a Foe: the Role of Cholesterol and its Metabolite in α-Synuclein Cell-to-Cell Transmission

We hypothesize that alterations in cholesterol levels or its metabolites can regulate the cell-to-cell transmission of α-synuclein. To test this hypothesis, we will utilize our recently developed P2A system enabling simultaneous detection of α-synuclein aggregation and transmission in neurons under pharmacological targeting of cellular cholesterol levels.

The proposed goal of the study is constructed with two specific aims. In Aim-1, we will explore the effects of pharmacological perturbations of neuronal cholesterol levels on α-synuclein transmission. In Aim-2, we will examine whether 24Shydroxycholesterol regulates α-synuclein aggregation and transmission.

Since our P2A transmission system is amendable for in vivo studies, successful results from this pilot study can progress towards testing cholesterol- or metabolite-reducing drugs as modulators of α-synuclein-induced toxicity and pathology in the mouse brain and the underlying mechanisms.