Structure-Function Studies of Amyloid Pores in Alzheimer's Disease as a Case Example of Neurodegenerative Diseases

Fernando Teran Arce, Hyunbum Jang, Laura Connelly, Srinivasan Ramachandran, Bruce L. Kagan, Ruth Nussinov, Ratnesh Lal

Research output: Chapter in Book/Report/Conference proceedingChapter

1 Scopus citations

Abstract

Amyloidogenic proteins, characterized by their ability to form fibrilar aggregates with β-sheet configurations, play an important role in several neurodegenerative diseases, including Alzheimer's disease. Although their exact mechanism of toxicity is not yet known, considerable experimental evidence, including planar lipid bilayer (BLM), calcium imaging, atomic force microscopy (AFM) and electron microscopy (EM), links small oligomers to membrane permeabilization, leading to cytotoxicity by loss of ionic homeostasis. A possible mechanism of this toxicity involves amyloids incorporated as pore-forming structures in the lipid environment of the membrane. Such pores produce stepwise increases in current across lipid bilayers in BLM data and can be recognized as small protrusions in AFM images. Unlike classic ion channels, these pores exhibit multiple ionic conductances and they have a variable number of subunits. Molecular dynamics (MD) simulations have provided atomistic models that capture the essential features of the pores. In these simulations, monomers adopt the U-shaped, β-strand-turn-β-strand motif as a general feature of amyloid organization.

Original languageEnglish (US)
Title of host publicationBio-nanoimaging
Subtitle of host publicationProtein Misfolding and Aggregation
PublisherElsevier Inc.
Pages397-408
Number of pages12
ISBN (Print)9780123944313
DOIs
StatePublished - Nov 2013
Externally publishedYes

Keywords

  • Amyloid
  • Atomic force microscopy
  • Cell homeostasis
  • Cell membrane
  • Electrophysiology
  • Fibrils
  • Ion-channel
  • Molecular dynamics simulations
  • Oligomers
  • Planar lipid bilayer
  • Protein aggregation
  • β-sheet

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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