# Cholesterol impairment contributes to neuroserpin aggregation

## TL;DR

This study reveals that cholesterol depletion promotes neuroserpin protein aggregation, potentially contributing to neurodegenerative diseases, by affecting membrane properties and protein clearance mechanisms.

## Contribution

It uncovers a novel link between cholesterol levels and neuroserpin aggregation, independent of genetic mutations, through combined experimental and computational approaches.

## Key findings

- Cholesterol depletion enhances neuroserpin aggregation.
- Reduced cholesterol impairs membrane vesicle formation.
- A decrease in protein clearance rate promotes aggregation.

## 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 regulatory 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.