Statins reduce neuronal α‐synuclein aggregation in in vitro models of Parkinson’s disease

Aggregation of α‐synuclein (α‐syn) is believed to play a critical role in the pathogenesis of disorders such as dementia with Lewy bodies and Parkinson’s disease. The function of α‐syn remains unclear, although several lines of evidence suggest that α‐syn is involved in synaptic vesicle trafficking probably via lipid binding. Moreover, interactions with cholesterol and lipids have been shown to be involved in α‐syn aggregation. In this context, the main objective of this study was to determine if statins – cholesterol synthesis inhibitors – might interfere with α‐syn accumulation in cellular models. For this purpose, we studied the effects of lovastatin, simvastatin, and pravastatin on the accumulation of α‐syn in a stably transfected neuronal cell line and in primary human neurons. Statins reduced the levels of α‐syn accumulation in the detergent insoluble fraction of the transfected cells. This was accompanied by a redistribution of α‐syn in caveolar fractions, a reduction in oxidized α‐syn, and enhanced neurite outgrowth. In contrast, supplementation of the media with cholesterol increased α‐syn aggregation in detergent insoluble fractions of transfected cells and was accompanied by reduced neurite outgrowth. Taken together, these results suggest that regulation of cholesterol levels with cholesterol inhibitors might be a novel approach for the treatment of Parkinson’s disease.