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

Abstract

Aggregation of a-synuclein (a-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 a-syn remains unclear, although several lines of evidence suggest that a-syn is involved in synaptic vesicle trafficking probably via lipid binding. Moreover, interactions with cholesterol and lipids have been shown to be involved in a-syn aggregation. In this context, the main objective of this study was to determine if statins -cholesterol synthesis inhibitors -might interfere with a-syn accumulation in cellular models. For this purpose, we studied the effects of lovastatin, simvastatin, and pravastatin on the accumulation of a-syn in a stably transfected neuronal cell line and in primary human neurons. Statins reduced the levels of a-syn accumulation in the detergent insoluble fraction of the transfected cells. This was accompanied by a redistribution of a-syn in caveolar fractions, a reduction in oxidized a-syn, and enhanced neurite outgrowth. In contrast, supplementation of the media with cholesterol increased a-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.

Differential effects of simvastatin and pravastatin on expression of Alzheimer's disease-related genes in human astrocytes and neuronal cells

“…For example, population studies suggested that statin users have signifi cantly lower risk of dementia, including AD ( 2,3 ), and clinical studies suggested that use of statins may also improve other neurological conditions, such as multiple sclerosis, Parkinson's disease, and traumatic brain injury (43)(44)(45)(46)(47). However, some studies of effects of statins on the brain and brain cells suggested that statins have potential not only to promote health but also to induce harm in the central nervous system.…”

SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis

“…Although there has been ambivalent evidence in the more distant past, a flurry of recent reports have clarified the detrimental effects of cholesterol accumulation in neurons (30)(31)(32). These studies are paralleled by evidence that increased neuronal cholesterol presents a risk factor for Alzheimer's and Parkinson's diseases (33)(34)(35). Although debated, it has also been proposed that neuronal cholesterol may be due to instrinsic biosynthesis (36), rather than transport from extracellular sources.…”

Specificity and Kinetics of α-Synuclein Binding to Model Membranes Determined with Fluorescent Excited State Intramolecular Proton Transfer (ESIPT) Probe

“…Effect of the Cholesterol on AS Binding-Cholesterol is an important component of cellular membranes (57,58) and also affects the binding of AS to membranes and the rate of AS aggregation (59,60). We analyzed the effect of cholesterol on the AS-membrane binding.…”