title: Cholesterol impairment contributes to neuroserpin 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 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.
authors.affiliation: FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Giampietro
authors.affiliation: Center for Complexity and Biosystems, Department of Biosciences, University of Milano, via Celoria 26, 20133 Milano, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Lionetti
authors.affiliation: Center for Complexity and Biosystems, Department of Physics, University of Milano, via Celoria 16, 20133 Milano, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Costantini
authors.affiliation: Center for Complexity and Biosystems, Department of Biosciences, University of Milano, via Celoria 26, 20133 Milano, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Mutti
authors.affiliation: Center for Complexity and Biosystems, Department of Physics, University of Milano, via Celoria 16, 20133 Milano, Italy.|CNR - Consiglio Nazionale delle Ricerche, Istituto di Chimica della Materia Condensata e di Tecnologie per l'Energia, Via R. Cozzi 53, 20125 Milano, Italy.|ISI Foundation, Via Alassio 11C, Torino, Italy.|Department of Applied Physics, Aalto University, P.O. Box 14100, FIN-00076, Aalto, Finland.
authors.forename: Stefano
authors.initials: S
authors.lastname: Zapperi
authors.affiliation: Center for Complexity and Biosystems, Department of Biosciences, University of Milano, via Celoria 26, 20133 Milano, Italy.
authors.forename: Caterina A M
authors.initials: CA
authors.lastname: La Porta
mesh_terms: D002784:Cholesterol / Q000378:metabolism*; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D042541:Intracellular Space / Q000378:metabolism; D008962:Models, Theoretical; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D066329:Protein Aggregates / Q000187:drug effects; D066263:Protein Aggregation, Pathological; D021381:Protein Transport; D015843:Serpins / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology; D000097522:Neuroserpin; D000094062:Betulinic Acid
chemical_list: D002784:Cholesterol; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009479:Neuropeptides; D066329:Protein Aggregates; D015843:Serpins; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014315:Triterpenes; D000097522:Neuroserpin; C002503:betulin; D000094062:Betulinic Acid