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Amyloid properties of the leader peptide of variant B cystatin C: implications for Alzheimer and macular degeneration
Author(s) -
Sant'Anna Ricardo,
Navarro Susanna,
Ventura Salvador,
Paraoan Luminita,
Foguel Debora
Publication year - 2016
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.12093
Subject(s) - cystatin c , macular degeneration , peptide , signal peptide , cystatin , pathogenesis , amyloid (mycology) , alzheimer's disease , mutation , fibril , chemistry , biology , medicine , disease , biochemistry , gene , pathology , peptide sequence , ophthalmology , renal function
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 .