Augmentation of Bri2 molecular chaperone activity against amyloid-β reduces neurotoxicity in mouse hippocampus in vitro

Autor:	Axel Abelein, Jan Johansson, Xueying Zhong, Gefei Chen, Axel Leppert, Henrik Biverstål, Hans Hebert, Yuniesky Andrade-Talavera, Per Nilsson, Michael Landreh, Simone Tambaro, André Fisahn, Harriet Nilsson
Jazyk:	angličtina
Rok vydání:	2020
Předmět:	Models Molecular 0301 basic medicine Amyloid Protein Conformation Mutant Medicine (miscellaneous) Peptide Hippocampus Article General Biochemistry Genetics and Molecular Biology Protein Aggregates Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Chaperones medicine lcsh:QH301-705.5 chemistry.chemical_classification Amyloid beta-Peptides biology Neurotoxicity Wild type Alzheimer's disease medicine.disease In vitro Kinesis Cell biology 030104 developmental biology chemistry lcsh:Biology (General) Chaperone (protein) biology.protein Protein quaternary structure Protein folding Protein aggregation Protein Multimerization General Agricultural and Biological Sciences 030217 neurology & neurosurgery Molecular Chaperones Protein Binding
Zdroj:	Communications Biology, Vol 3, Iss 1, Pp 1-12 (2020) Communications Biology
ISSN:	2399-3642
DOI:	10.1038/s42003-020-0757-z
Popis:	Molecular chaperones play important roles in preventing protein misfolding and its potentially harmful consequences. Deterioration of molecular chaperone systems upon ageing are thought to underlie age-related neurodegenerative diseases, and augmenting their activities could have therapeutic potential. The dementia relevant domain BRICHOS from the Bri2 protein shows qualitatively different chaperone activities depending on quaternary structure, and assembly of monomers into high-molecular weight oligomers reduces the ability to prevent neurotoxicity induced by the Alzheimer-associated amyloid-β peptide 1-42 (Aβ42). Here we design a Bri2 BRICHOS mutant (R221E) that forms stable monomers and selectively blocks a main source of toxic species during Aβ42 aggregation. Wild type Bri2 BRICHOS oligomers are partly disassembled into monomers in the presence of the R221E mutant, which leads to potentiated ability to prevent Aβ42 toxicity to neuronal network activity. These results suggest that the activity of endogenous molecular chaperones may be modulated to enhance anti-Aβ42 neurotoxic effects. Gefei Chen et al. show that a mutated BRICHOS molecular chaperone domain from the dementia associated Bri2 can reduce toxicity of amyloid formation in mouse hippocampus in vitro. Upon mutating Arg221 to glutamate, Bri2 BRICHOS forms stable monomers that block a source of neurotoxicity during Aβ aggregation and promote disassembly of wild-type oligomers.
Databáze:	OpenAIRE
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