Abstract
Intraneural accumulation of misfolded proteins is a common feature of several neurodegenerative pathologies including Alzheimer’s and Parkinson’s diseases, and Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). FENIB is a rare disease due to a point mutation in neuroserpin which accelerates protein aggregation in the endoplasmic reticulum (ER). Here we show that cholesterol depletion induced either by prolonged exposure to statins or by inhibiting the sterol reg-ulatory binding-element protein (SREBP) pathway also enhances aggregation of neuroserpin proteins. These findings can be explained considering a computational model of protein aggregation under non-equilibrium conditions, where a decrease in the rate of protein clearance improves aggregation. Decreasing cholesterol in cell membranes affects their biophysical properties, including their ability to form the vesicles needed for protein clearance, as we illustrate by a simple mathematical model. Taken together, these results suggest that cholesterol reduction induces neuroserpin aggregation, even in absence of specific neuroserpin mutations. The new mechanism we uncover could be relevant also for other neurodegenerative diseases associated with protein aggregation.
Highlights
Cholesterol plays a crucial role in regulating the properties of phospholipid membranes, affecting their fluidity and rigidity[21,22,23], the function and dynamics of membrane proteins[24,25], and vesicular trafficking within the cell[26,27,28]
The mature processed form of SREBP is released in the cytosol and can translocate into the nucleus where it modulates the expression of several genes controlling cholesterol and fatty acid homeostasis[33], including HMGCR, HMG-CoA synthase (HMGCS), low density lipoprotein receptor (LDLR) and SREBP1/2 itself
We combine experiments and computational analysis to show that lowering the level of cholesterol either by using statins or by inhibiting SREBP1 and SREBP2 pathways with the small molecule betulin has a significant impact on the aggregation of non-mutated neuroserpin within the cell
Summary
Cholesterol plays a crucial role in regulating the properties of phospholipid membranes, affecting their fluidity and rigidity[21,22,23], the function and dynamics of membrane proteins[24,25], and vesicular trafficking within the cell[26,27,28]. We combine experiments and computational analysis to show that lowering the level of cholesterol either by using statins or by inhibiting SREBP1 and SREBP2 pathways with the small molecule betulin has a significant impact on the aggregation of non-mutated neuroserpin within the cell. To confirm the direct involvement in aggregation of lower cholesterol levels, we use betulin, a pentacyclic triterpene commonly isolated from the birch bark, that inhibits the maturation of SREBPs by enhancing interaction between SCAP and INSIG promoting SREBPs retention in the ER40. In this case, we observe lower cholesterol and more neuroserpin aggregation. Our results suggest that long-term treatment with statins may affect intracellular trafficking in a way to enhance protein aggregation
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