PXD036416

PXD036416 is an original dataset announced via ProteomeXchange.

Title	Domino-like Effect of C112R Mutation on APOE4 Aggregation and Its Suppression by Alzheimer’s Disease Drug Candidate
Description	The development of treatment for Alzheimer’s Disease (AD) is hindered by a limited understanding of its structural basis. Apolipoprotein E (APOE) ε4 genotype is the most important risk factor for late-onset AD. APOE4 differs from the APOE3 isoform by a single mutation, C112R. Here, we employ crystallography, biophysical methods and computer simulations to dissect the “domino-like” effect of C112R substitution on APOE4 behaviour. We found that the mutation induces long-distance (>15 Å) conformational changes leading to geometrically distinct T-shaped dimeric unit of APOE4 compared to APOE3. By mutagenesis, we demonstrate that the APOE4 unit is more prone to aggregation than that of the APOE3. AD drug candidate tramiprosate and metabolite 3-sulfopropanoic acid induce APOE3-like conformational behaviour in APOE4 and suppress its aggregation propensity. Omics analysis of APOE ε4/ε4 cerebral organoids treated with tramiprosate revealed its effect on cholesteryl esters, the storage product of excess cholesterol. Our results connect the APOE4 structure with its aggregation propensity, which can be further exploited in drug development for neurodegeneration and ageing.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:02:31.922.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Lenka Hernychova
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-30 14:28:53	ID requested
1	2023-07-20 10:45:42	announced
⏵ 2	2023-11-14 09:02:40	announced	2023-11-14: Updated project metadata.

Nemergut M, Marques SM, Uhrik L, Vanova T, Nezvedova M, Gadara DC, Jha D, Tulis J, Novakova V, Planas-Iglesias J, Kunka A, Legrand A, Hribkova H, Pospisilova V, Sedmik J, Raska J, Prokop Z, Damborsky J, Bohaciakova D, Spacil Z, Hernychova L, Bednar D, Marek M, Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer's Disease drug candidate. Mol Neurodegener, 18(1):38(2023) [pubmed]

submitter keyword: molecular dynamics, LC-MSMS, Alzheimer’s disease,Ageing, Apolipoprotein E, HDX-MS

Prof. Jiri Damborsky
contact affiliation	Loschmidt Laboratories Department of Experimental Biology & RECETOX Faculty of Science, Masaryk University
contact email	jiri@chemi.muni.cz
lab head
Lenka Hernychova
contact affiliation	Masaryk Memorial Cancer Institutre, Zluty kopec 7, Brno 656 53, Czech Republic
contact email	lenka.hernychova@mou.cz
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/07/PXD036416

PRIDE project URI

• PRIDE
  1. PXD036416
     1. Label: PRIDE project
     2. Name: Domino-like Effect of C112R Mutation on APOE4 Aggregation and Its Suppression by Alzheimer’s Disease Drug Candidate