title: Amyloid properties of the leader peptide of variant B cystatin C: implications for Alzheimer and macular degeneration.
abstract: Variant B (VB) of cystatin C has a mutation in its signal peptide (A25T), which interferes with its processing leading to reduced secretion and partial retention in the vicinity of the mitochondria. There are genetic evidences of the association of VB with Alzheimer's disease (AD) and age-related macular degeneration (AMD). Here, we investigated aggregation and amyloid propensities of unprocessed VB combining computational and in vitro studies. Aggregation predictors revealed the presence of four aggregation-prone regions, with a strong one at the level of the signal peptide, which indeed formed toxic aggregates and mature amyloid fibrils in solution. In light of these results, we propose for the first time the role of the signal peptide in pathogenesis of AD and AMD.
authors: Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors: Ricardo
authors: R
authors: Sant'Anna
authors: Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors: Susanna
authors: S
authors: Navarro
authors: Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors: Salvador
authors: S
authors: Ventura
authors: Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, UK.
authors: Luminita
authors: L
authors: Paraoan
authors: Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Estrutural, Universidade Federal do Rio de Janeiro, Brazil.
authors: Debora
authors: D
authors: Foguel
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D058227:Amyloidogenic Proteins / Q000737:chemistry*; D019295:Computational Biology; D055316:Cystatin C / Q000737:chemistry*; D006801:Humans; D008268:Macular Degeneration / Q000378:metabolism*; D008969:Molecular Sequence Data; D066329:Protein Aggregates; D021382:Protein Sorting Signals; D017433:Protein Structure, Secondary; D012306:Risk
chemical_list: D058227:Amyloidogenic Proteins; D055316:Cystatin C; D066329:Protein Aggregates; D021382:Protein Sorting Signals
keywords: Alzheimers' disease and exudative age-related macular degeneration; human cystatin C; protein aggregation