PXD062542-1

PXD062542 is an original dataset announced via ProteomeXchange.

Title	Proteomic analysis of patient tissue reveals parallels and discrepancies in immune and mitochondrial processes across mouse models of motor neurone disease
Description	Motor neurone disease (MND) is a fatal neurodegenerative disease resulting in the progressive loss of motor neurons in the brain and spine. More than 95% of cases are pathologically characterized by the cytoplasmic accumulation of hyperphosphorylated and ubiquitinated transactive response DNA-binding protein 43 (TDP-43). Multiple mouse models showing TDP-43 accumulation have been developed, however, whether they recapitulate molecular features of MND pathology is unclear. Given the lack of curative treatment for MND, there is an urgent need to identify the precise biological processes contributing to disease pathogenesis for the development of effective therapeutic treatments. To explore the complexity of MND, we employed label-based untargeted proteomics to quantify 7,946 proteins from the spinal cord and brain of TDP-43Q331K mice, a transgenic mouse model of MND. These findings were compared to the human sporadic MND proteome from the motor cortex, as well as the cervical, thoracic, and lumbar spinal cord regions. These data were analyzed for differentially expressed proteins (DEPs) and their associated biological processes. To identify mouse models that show higher concordance with our human dataset, we performed a meta-analysis of previously published proteomics datasets. In mice, we demonstrate unique and overlapping features in the brain and spinal cord, with a total of 76 DEPs identified in WT littermates versus TDP-43Q331K mice. These protein signatures were associated with a wide range of cellular processes including metabolism, mitochondrial function, muscle contraction, synaptic and neurotransmitter signaling. In humans, we observed highly overlapping responses across the four tissues examined, primarily related to the upregulation of immune processes and the downregulation of mitochondrial function. In contrast, in TDP-43Q331K mice we demonstrate a lack of enrichment for immune activation and the opposite regulation of mitochondrial processes. An examination of previously published mouse datasets identified the Ubqln2 knock-out mouse model as showing stronger parallels with our late-stage human MND. Overall, this study provides in-depth analysis of the site-specific dysregulated proteomes and their associated functional processes across species. Thereby, identifying potential therapeutic targets while emphasizing the limitations of specific mouse models in recapitulating certain MND-related processes for future model development.
HostingRepository	PRIDE
AnnounceDate	2025-10-06
AnnouncementXML	Submission_2025-10-05_18:44:55.385.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Han Lee
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606; scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-02 19:46:10	ID requested
⏵ 1	2025-10-05 18:44:56	announced

Spiteri AG, Steele JR, Lee HC, Zhang H, Sun J, Schittenhelm RB, Yu CH, McLean C, Masters CL, Goudey B, Jin L, Pan Y, Proteomic analysis of brain and spinal cord tissue reveals distinct immune and mitochondrial processes between human and mouse ALS models. Sci Rep, 15(1):33959(2025) [pubmed]

10.1038/s41598-025-11466-0;

submitter keyword: Motor neurone disease

Amyotrophic lateral sclerosis

Immune-mediated pathology

Mitochondrial dysfunction

Neurodegeneration

TDP-43

TMT-proteomics.

Yijun Pan, PhD
contact affiliation	Florey Institute, University of Melbourne, Parkville, Victoria 3052, Australia
contact email	yijun.pan@unimelb.edu.au
lab head
Han Lee
contact affiliation	Monash Proteomics & Metabolomics Facility
contact email	han.lee@monash.edu
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/2025/10/PXD062542

PRIDE project URI

• PRIDE
  1. PXD062542
     1. Label: PRIDE project
     2. Name: Proteomic analysis of patient tissue reveals parallels and discrepancies in immune and mitochondrial processes across mouse models of motor neurone disease