Amyloid properties of the leader peptide of variant B cystatin C: implications for Alzheimer and macular degeneration

Ricardo Sant'Anna, Susanna Navarro, Salvador Ventura, Luminita Paraoan, Debora Foguel

Research output: Contribution to journalArticle (journal)peer-review

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)644-54
Number of pages11
JournalFEBS Letters
Volume590
Issue number5
DOIs
Publication statusPublished - 10 Feb 2016
Externally publishedYes

Keywords

  • Alzheimer Disease/metabolism
  • Amino Acid Sequence
  • Amyloidogenic Proteins/chemistry
  • Computational Biology
  • Cystatin C/chemistry
  • Humans
  • Macular Degeneration/metabolism
  • Molecular Sequence Data
  • Protein Aggregates
  • Protein Sorting Signals
  • Protein Structure, Secondary
  • Risk

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