Possible link between cholesterol and neurodegenerative diseases
A prolonged decrease in the cholesterol content of cell membranes may provoke an abnormal accumulation of proteins. And that, in turns, might lay the ground for the insurgence of a neurodegenerative disease. This is the striking result of a study carried out on cultured cells by a group of scientists from the CC&B, led by Caterina La Porta. The results have been published in Scientific Reports.
With cardiovascular diseases being the first cause of death worldwide, reducing cholesterol levels in the blood is one of the primary strategy against circulatory problems. And statins have proven very effective in doing that. But what happens when such a decrease occurs not in the blood, but in the cellular membranes? Cholesterol is known to play a crucial role in regulating the properties of cell membranes, affecting their fluidity and rigidity. Hence, by regulating its biosynthesis it would be possible to affect the form and function of all the membranes within the cell. La Porta and her colleagues combined biological experiments and mathematical simulations in order to provide an answer to this question. They tested three different statins – SIM, rosuvastatin and PRA – and betulin, an inhibitor of two proteins that controls cholesterol concentration, on cultured cells. Their results, published on Scientific Reports, show that depleting cholesterol, both through statins or betulin, induced the aggregation of a protein called neuroserpin. Neuroserpin is quite an important protein, for it plays a relevant role in brain development and neuronal survival. Mutations in the gene coding for neuroserpin produce abnormal versions of this protein, which may attach to one another forming anomalous aggregations within neurons. These clumps, in turns, provoke a progressive disorder of the nervous system called FENIB, which stands for “Familial encephalopathy with neuroserpin inclusion bodies”, an extremely rare neurodegenerative disease characterized by dementia and seizures. However, the experiments carried out by La Porta and her colleagues were performed on cultured cells with no mutations on the neuroserpin gene. Meaning that a chronic exposure to substances that decrease cholesterol levels in the cell membranes led to a dramatic increase in neuroserpin aggregates, regardless of genetics.
To elucidate the mechanism underlying this observation, the researchers developed a simple mathematical model, which they used to test a specific hypothesis. As mentioned before, cholesterol has an effect on some properties of cell membranes and its depletion could impair the formation of small cellular structures called vesicles, which are used to transport materials within the cells. According to the researchers’ model, it is possible that small changes of key membrane parameters, induced by prolonged low levels of cholesterol, will result in a net impairment of vesicle formation, which in turns may lead to neuroserpin aggregation. Even in the absence of deleterious mutations that are known to induce aggregation of this protein. Taken together, these results suggest that long-term treatment with statins may affect intracellular trafficking in a way to enhance neuroserpin aggregation. Which does not mean that taking statins will eventually result in the onset of a serious neurodegenerative disorder such as FENIB. However, protein aggregations are not a physiological phenomenon and, besides, neuroserpin is not the only protein that may be affected. “We focused our attention on neuroserpin but the alteration of the cell membranes and the intracellular transport system might provoke the aggregation of other proteins,” say Caterina La Porta. “Moreover, neuroserpin aggregation has been also associated with other neurodegenerative diseases that are more common than the very rare FENIB, for instance Alzheimer’s disease”.While we know that lowering cholesterol levels in the blood may reduce the risk of cardiovascular events, the consequences of chronic cholesterol depletion on the cell membranes were still unclear.“What we have demonstrated in this paper is that neuroserpin without mutation can aggregate under specific environmental conditions, such as cholesterol impairment,” concludes La Porta. “However, further studies will be needed to better understand the interplay between cholesterol, cell membranes properties and protein aggregations”.