| First Author | Min JO | Year | 2023 |
| Journal | Cell Death Dis | Volume | 14 |
| Issue | 7 | Pages | 474 |
| PubMed ID | 37500624 | Mgi Jnum | J:354493 |
| Mgi Id | MGI:7513120 | Doi | 10.1038/s41419-023-05977-9 |
| Citation | Min JO, et al. (2023) Statins suppress cell-to-cell propagation of alpha-synuclein by lowering cholesterol. Cell Death Dis 14(7):474 |
| abstractText | 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. |
