Phospholipids and Cholesterol Determine Molecular Mechanisms of Cytotoxicity of -Synuclein Oligomers and Fibrils

Progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta, hypothalamus, and thalamus is a hallmark of Parkinson's disease. Neuronal death is linked to the abrupt aggregation of alpha-synuclein (alpha-Syn), a small membrane protein that regulates cell vesicle trafficking. alpha-Syn aggregation rate, as well as the secondary structure and toxicity of alpha-Syn fibrils, could be uniquely altered by lipids. However, molecular mechanisms that determine such a remarkable difference in the toxicity of alpha-Syn fibrils formed in the presence of lipids remain unclear. In this study, we used a set of molecular assays to determine the molecular mechanism by which alpha-Syn fibrils formed in the presence of phosphatidylcholine (PC), cardiolipin (CL), and cholesterol (Cho) exert cell toxicity. We found that rat dopaminergic cells exposed to alpha-Syn fibrils formed in the presence of different lipids exert drastically different magnitudes and dynamics of unfolded protein response (UPR) in the endoplasmic reticulum (ER) and mitochondria (MT). Specifically, alpha-Syn:CL were found to cause the strongest, whereas alpha-Syn fibrils formed in the absence of lipids had the lowest magnitude of the UPR cell response. We also found the opposite dynamics of the ER- and MT-UPR responses in rat dopaminergic cells exposed to protein aggregates. These results could suggest that facing severe ER stress, dopaminergic cells suppress MT-UPR response, enabling the maximal ATP production to restore their normal physiological function. These findings help to better understand complex mechanisms of cell toxicity of amyloid aggregates and ultimately find neuroprotective drug candidates that will be able to suppress the spread of Parkinson's disease.