TY - GEN

T1 - Identification and characterization of mutations influencing aggregation of human Aβ peptide in the yeast model

AU - Rubel, Aleksandr A.

AU - Malikova, Oksana A.

AU - Zobnina, Anastasia E.

AU - Kachkin, Daniel V.

AU - Чернов, Юрий Олегович

AU - Lashkul, Veronika V.

AU - Chernoff, Yury O.

PY - 2020/12/2

Y1 - 2020/12/2

N2 - Alzheimer's disease (AD) is the most common form of dementia, that islinked to neuron degeneration and death. Heritable AD is caused bymutations, influencing production and/or oligomerization and amyloidaggregation of the Aβ peptide, while sporadic AD is associated withspontaneous oligomerization and amyloid formation by Aβ, and usuallyaffects aged people. Understanding of the role of specific amino acidresidues in oligomerization and amyloid formation by Aβ is thereforecrucial for deciphering mechanisms, leading to the development of AD. Wehave employed the yeast-based assay for the large-scale screening for Aβmutations influencing amyloid nucleation. This assay is based onphenotypic detection of amyloid aggregation, nucleated by the attachmentof Aβ to prion domain of the yeast protein Sup35 in yeast(Chandramowlishwaran et al. 2018 J. Biol. Chem. 293:3436). Several dozenAβ derivatives with single or multiple mutations, altering amyloidnucleation were uncovered by this screen. Some mutations occurred at sitespreviously 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 cytologicalparameters of Aβ aggregates, as well on the Aβ amyloid structure derivedfrom experimental studies and/or predicted by computational algorithmshave been investigated. Results of these experiments shed light on modesand pathways of Aβ oligomerization and aggregation.This study was supported by grant 19-34-51054 from Russian Foundationfor Basic Research. Authors acknowledge technical support from theSPbSU Resource Centers “Chromas”, “Molecular and Cell Technologies”,and “Biobank”.

AB - Alzheimer's disease (AD) is the most common form of dementia, that islinked to neuron degeneration and death. Heritable AD is caused bymutations, influencing production and/or oligomerization and amyloidaggregation of the Aβ peptide, while sporadic AD is associated withspontaneous oligomerization and amyloid formation by Aβ, and usuallyaffects aged people. Understanding of the role of specific amino acidresidues in oligomerization and amyloid formation by Aβ is thereforecrucial for deciphering mechanisms, leading to the development of AD. Wehave employed the yeast-based assay for the large-scale screening for Aβmutations influencing amyloid nucleation. This assay is based onphenotypic detection of amyloid aggregation, nucleated by the attachmentof Aβ to prion domain of the yeast protein Sup35 in yeast(Chandramowlishwaran et al. 2018 J. Biol. Chem. 293:3436). Several dozenAβ derivatives with single or multiple mutations, altering amyloidnucleation were uncovered by this screen. Some mutations occurred at sitespreviously 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 cytologicalparameters of Aβ aggregates, as well on the Aβ amyloid structure derivedfrom experimental studies and/or predicted by computational algorithmshave been investigated. Results of these experiments shed light on modesand pathways of Aβ oligomerization and aggregation.This study was supported by grant 19-34-51054 from Russian Foundationfor Basic Research. Authors acknowledge technical support from theSPbSU Resource Centers “Chromas”, “Molecular and Cell Technologies”,and “Biobank”.

M3 - Conference contribution

SP - 272

BT - Neurodegenerative Diseases: Biology & Therapeutics

PB - Cold Spring Harbor Laboratory

T2 - Neurodegenerative Diseases: Biology & Therapeutics

Y2 - 2 December 2020 through 4 December 2020

ER -