Statins suppress cell-to-cell propagation of & alpha;-synuclein by lowering cholesterol

Cell-to-cell propagation of protein aggregates has been implicated in the progression of neurodegenerative diseases. However, the underlying mechanism and modulators of this process are not fully understood. Here, we screened a small-molecule library in a search for agents that suppress the propagation of & alpha;-synuclein and mutant huntingtin (mHtt). These screens yielded several molecules, some of which were effective against both & alpha;-synuclein and mHtt. Among these molecules, we focused on simvastatin and pravastatin. Simvastatin administration in a transgenic model of synucleinopathy effectively ameliorated behavioral deficits and & alpha;-synuclein accumulation, whereas pravastatin had no effect. Because only simvastatin enters the brain effectively, these results suggest that inhibition of brain cholesterol synthesis is important in simvastatin effects. In cultured cells, accumulation of intracellular cholesterol, induced by genetic ablation of the NPC1 gene or by pharmacological treatment with U18666A, increased & alpha;-synuclein aggregation and secretion. In contrast, lowering cholesterol using methyl-& beta;-cyclodextrin or statins reversed & alpha;-synuclein aggregation and secretion in NPC1-knockout cells. Consistent with these observations, feeding a high-fat diet aggravated & alpha;-synuclein pathology and behavioral deficits in the preformed fibril-injected mouse model, an effect that was also reversed by simvastatin administration. These results suggest that statins suppress propagation of protein aggregates by lowering cholesterol in the brain.

Automated summary

Cell-to-cell propagation of protein aggregates is involved in the progression of neurodegenerative diseases. We screened a small-molecule library and identified simvastatin as a potential agent that suppresses the propagation of α-synuclein and mutant huntingtin. Simvastatin effectively improved behavioral deficits and reduced α-synuclein accumulation in a synucleinopathy model, suggesting the importance of inhibiting brain cholesterol synthesis in its effects.