PXD044942-1

PXD044942 is an original dataset announced via ProteomeXchange.

Title	Lysosomal proteomics reveals mechanisms of neuronal apoE4 - 2 associated lysosomal dysfunction
Description	The E4 variant of APOE is the primary risk factor for Alzheimer’s Disease. While APOE is primarily expressed by astrocytes, early AD pathology appears predominantly in neurons, including endosomal abnormalities and mitochondrial dysfunction. Lysosomes are poised at the convergence point between these distinct features, orchestrating clearance of defective mitochondria. Here we find that Neuro-2a cells expressing apoE4 exhibit lysosomal alkalinization, reduced lysosomal proteolysis, and reduced mitophagy as compared to apoE3-expressing cells. To identify factors that may regulate this lysosomal dysfunction we performed quantitative proteomic profiling of lysosomes. This revealed that apoE4 expression results in the depletion of Lgals3bp and the accumulation of Tmed5 in both Neuro-2a cells and postmitotic human neurons, as compared to apoE3. Modulation of expression of both proteins was found to regulate lysosomal function, with knockdown of Tmed5 in apoE4 cells rescuing lysosomal alkalinization, while knockdown of Lgals3bp in apoE3 cells promoted lysosomal alkalinization and reduced lysosomal density. Taken together, our work reveals that the apoE4 allele exerts gain-of-toxicity by alkalinizing the lysosomal lumen, and pinpoints lysosomal Tmed5 accumulation and Lgals3bp depletion as apoE4-associated drivers for this phenotype.
HostingRepository	PRIDE
AnnounceDate	2026-01-12
AnnouncementXML	Submission_2026-01-11_16:50:56.884.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Justin McKetney
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-29 16:10:26	ID requested
⏵ 1	2026-01-11 16:50:58	announced

10.1080/15548627.2025.2576613;

Krogsaeter EK, McKetney J, Valiente-Banuet L, Marquez A, Willis A, Cakir Z, Stevenson E, Jang GM, Rao A, Li E, Zhou A, Attili A, Chang TS, Kampmann M, Huang Y, Krogan NJ, Swaney DL, Lysosomal proteomics reveals mechanisms of neuronal APOE4-associated lysosomal dysfunction. Autophagy, 21(12):3240-3265(2025) [pubmed]

submitter keyword: Lgals3bp, APMS, mass spectrometry,APOE 4 , Alzheimer’s Disease, Lysosomes

Nevan J Krogan
contact affiliation	QBI Director and Professor in Cellular and Molecular Pharmacology, UCSF
contact email	nevan.krogan@ucsf.edu
lab head
Justin McKetney
contact affiliation	University of California, San Francisco
contact email	justinmcketney@gmail.com
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/2026/01/PXD044942

PRIDE project URI

• PRIDE
  1. PXD044942
     1. Label: PRIDE project
     2. Name: Lysosomal proteomics reveals mechanisms of neuronal apoE4 - 2 associated lysosomal dysfunction