PXD065459-1

PXD065459 is an original dataset announced via ProteomeXchange.

Title	CZE-MS/MS-based quantitative top-down proteomics reveals significant proteoform differences between healthy and Alzheimer's disease human brains
Description	Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline and pathological protein aggregation. Comprehensive protein characterization of human brains of AD patients and comparison with healthy samples is critical for pursuing a better understanding of the molecular mechanisms that drive AD progression. Although many large-scale bottom-up proteomics studies of AD brains have been conducted, there are limited top-down proteomics (TDP) studies of human AD brains. This study employs CZE-MS/MS-based label-free quantitative TDP to profile proteoform differences in postmortem brain tissues from AD patients and healthy controls. Using a robust size exclusion chromatography (SEC) fractionation-CZE-MS/MS platform, we identified 3,191 unique proteoforms, uncovering distinct proteoform signatures between AD and healthy subjects. Principal component analysis (PCA) and hierarchical clustering revealed clear segregation of AD samples, driven by disease-specific changes in proteoform abundance . Notably, AD tissues exhibited elevated phosphorylation and combinatorial post-translational modifications (PTMs), including hyperphosphorylated tau and modified neurogranin proteoforms, which are implicated in synaptic dysfunction and neurodegeneration. Bidirectional regulation of proteoforms from key proteins such as Calmodulin-1 and MAPT further highlights the functional divergence in AD pathogenesis. Pathway analysis linked upregulated proteoforms in AD to amyloid fibril formation and microtubule disruption, while healthy samples were enriched for synaptic transmission and axogenesis pathways. These findings underscore the critical role of proteoform-specific alterations in AD pathology, offering new insights into molecular mechanisms and potential therapeutic targets.
HostingRepository	PRIDE
AnnounceDate	2025-11-21
AnnouncementXML	Submission_2025-11-21_10:41:05.148.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Liangliang Sun
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monomethylated residue; phosphorylated residue; acetylated residue; monohydroxylated residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-06-25 12:35:52	ID requested
⏵ 1	2025-11-21 10:41:06	announced

10.1002/pmic.70041;

Falamarzi Askarani M, Fang F, Counts SE, Sun L, Coupling CZE, Liquid-Phase Ion Mobility, to MS/MS for Quantitative Top-Down Proteomics: Revealing Significant Proteoform Differences Between Healthy and Alzheimer's Disease Brains. Proteomics, ():e70041(2025) [pubmed]

submitter keyword: top-down proteomics, human brain, proteoform, tau phosphorylation.,CZE-MS/MS, Alzheimer's Disease

Liangliang Sun
contact affiliation	1Department of Chemistry, Michigan State University, 578 S Shaw Lane, East Lansing, Michigan 48824, USA
contact email	lsun@chemistry.msu.edu
lab head
Liangliang Sun
contact affiliation	Michigan State University
contact email	lsun@chemistry.msu.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD065459
     1. Label: PRIDE project
     2. Name: CZE-MS/MS-based quantitative top-down proteomics reveals significant proteoform differences between healthy and Alzheimer's disease human brains