The Parkinson's disease-associated protein α-synuclein (α-syn) is not only expressed in the cytoplasm of neurons, but also secreted in the extracellular space and internalized into glial cells through a lipid raft dependent process. Two distinct cholesterol-binding domains in α-synuclein were identified by Fantini and coworkers. The tilted peptide of α-synuclein (67-78) bound cholesterol with high affinity and was toxic for cultured astrocytes. A cholesterol recognition consensus motif with lower affinity for cholesterol and devoid of toxicity, is encased in the glycosphingolipid-binding domain (34-45) of α-synuclein. The authors propose that the association of α-synuclein with lipid rafts involves both the binding of α-synuclein (34-45) to glycosphingolipids, and the interaction of α-synuclein (67-78) with cholesterol.
J.Fantini et al., Biochim. Biophys. Acta, 1808, 2343 (2011)