Identification and characterization of mutations influencing aggregation of human Aβ peptide in the yeast model

Aleksandr A. Rubel, Oksana A. Malikova, Anastasia E. Zobnina, Daniel V. Kachkin, Юрий Олегович Чернов, Veronika V. Lashkul, Yury O. Chernoff

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Abstract

Alzheimer's disease (AD) is the most common form of dementia, that is
linked to neuron degeneration and death. Heritable AD is caused by
mutations, influencing production and/or oligomerization and amyloid
aggregation of the Aβ peptide, while sporadic AD is associated with
spontaneous oligomerization and amyloid formation by Aβ, and usually
affects aged people. Understanding of the role of specific amino acid
residues in oligomerization and amyloid formation by Aβ is therefore
crucial for deciphering mechanisms, leading to the development of AD. We
have employed the yeast-based assay for the large-scale screening for Aβ
mutations influencing amyloid nucleation. This assay is based on
phenotypic detection of amyloid aggregation, nucleated by the attachment
of Aβ to prion domain of the yeast protein Sup35 in yeast
(Chandramowlishwaran et al. 2018 J. Biol. Chem. 293:3436). Several dozen
Aβ derivatives with single or multiple mutations, altering amyloid
nucleation were uncovered by this screen. Some mutations occurred at sites
previously linked to either heritable AD or amyloid formation in vitro,
while other mutations marked new sites with previously unknown roles.
Effects of most interesting mutations on biochemical and cytological
parameters of Aβ aggregates, as well on the Aβ amyloid structure derived
from experimental studies and/or predicted by computational algorithms
have been investigated. Results of these experiments shed light on modes
and pathways of Aβ oligomerization and aggregation.
This study was supported by grant 19-34-51054 from Russian Foundation
for Basic Research. Authors acknowledge technical support from the
SPbSU Resource Centers “Chromas”, “Molecular and Cell Technologies”,
and “Biobank”.
Original languageEnglish
Title of host publication Neurodegenerative Diseases: Biology & Therapeutics
Subtitle of host publicationAbstracts
PublisherCold Spring Harbor Laboratory Press
Pages272
StatePublished - 2 Dec 2020
EventNeurodegenerative Diseases: Biology & Therapeutics -
Duration: 2 Dec 20204 Dec 2020

Conference

ConferenceNeurodegenerative Diseases: Biology & Therapeutics
Period2/12/204/12/20

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