Atomic view of an amyloid dodecamer exhibiting selective cellular toxic vulnerability in acute brain slices
Year: 2021
Type: article
Abstract: Atomic structures of amyloid oligomers that capture the neurodegenerative disease pathology are essential to understand disease-state causes and finding cures. Here we investigate the G6W mutation of the cytotoxic, hexameric amyloid model KV11. The mutation results into an asymmetric dodecamer composed of a pair of 30° twisted antiparallel β-sheets. The complete break between adjacent β-strands is unprecedented among amyloid fibril crystal structures and supports that our structure is an oligomer. The poor shape complementarity between mated sheets reveals an interior channel for binding lipids, suggesting that the toxicity may be due to a perturbation of lipid transport rather than a direct disruption of membrane integrity. Viability assays on mouse suprachiasmatic nucleus, anterior hypothalamus, and cerebral cortex demonstrated selective regional vulnerability consistent with Alzheimer's disease. Neuropeptides released from the brain slices may provide clues to how G6W initiates cellular injury.
Source: Protein Science
DOI: 10.1002/pro.4268
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G152310409, G1742171491, G179862484, G218092134, G2206590661, G3226045097, XSEDE 2.0: Integrating, Enabling and Enhancing National Cyberinfrastructure with Expanding Community Involvement, G4155925329, Synthetic Lipid Switches for Controlling Liposome Assembly and Release, G6056929667, G633452075, G6806689448, G78868261, G8423653713, G9000051782, Towards Treatment of Alzheimer’s Disease by Targeting Pathogenic Tau and Beta-Amyloid Structures, NE-CAT: A Resource for Advanced Macromolecular Crystallography
OpenAlex ID: W4200050574