PXD066064

PXD066064 is an original dataset announced via ProteomeXchange.

Title	Disruption of astrocyte-neuron crosstalk in PSP: Integrated evidence from proteomics and MRS
Description	Progressive supranuclear palsy (PSP) is a tauopathy that presents region-specific patterns of neurodegeneration, affecting cortical and subcortical areas with relative selectivity. Among these, the anterior cingulate cortex (ACC) is of particular interest due to its involvement in executive functions, which are frequently impaired in PSP. However, the pathophysiological mechanisms underlying such selective vulnerability remain poorly understood. Given the integration of astrocytes into neural circuits, we hypothesized that astrocyte dysfunction and disrupted astrocyte–neuron crosstalk contribute to the metabolic and functional abnormalities observed in the ACC of PSP. To test this hypothesis, we conducted a multimodal analysis integrating SWATH-MS-based proteomics, histopathology, and in vivo magnetic resonance spectroscopy (MRS) in postmortem and living brains of PSP patients and controls. Astrocyte markers GFAP and AQP4 were significantly elevated in PSP-ACC, whereas neuronal markers remained unchanged. AQP4 expression exhibited polarity loss and negatively correlated with neuronal proteins, suggesting glymphatic dysfunction and glial–neuronal uncoupling. Proteomic analysis further revealed upregulation of enzymes related to the IP3–Ca²⁺ signaling cascade and downregulation of calcium extrusion pathways, indicating enhanced astrocytic Ca²⁺ signaling. This was consistent with elevated myo-inositol levels detected by MRS. MRS also revealed significantly increased lactate and glutamate levels in PSP-ACC. Proteomic data showed reduced expression of oxidative phosphorylation–related proteins (e.g., ETFDH, UQCRC1) and pyruvate dehydrogenase components (DLD, PDHX), particularly in astrocytes. These changes correlated with in vivo lactate and myo-inositol concentrations, indicating astrocyte-based metabolic failure. Furthermore, expression of glutamate–glutamine cycle molecules negatively correlated with GFAP and AQP4 levels, suggesting that astrocytic dysfunction underlies impaired excitatory/inhibitory balance. Taken together, these findings demonstrate that multiple aspects of astrocyte–neuron crosstalk—including glymphatic clearance, calcium signaling, mitochondrial metabolism, and neurotransmitter cycling—are selectively impaired in the ACC of PSP. These disruptions likely precede or exacerbate neuronal dysfunction in this region. Our study highlights astrocyte dysfunction as a central feature of PSP pathophysiology and suggests that MRS-detectable metabolites such as myo-inositol and lactate may serve as early, non-invasive biomarkers of glial dysfunction and circuit-level vulnerability in neurodegenerative tauopathies.
HostingRepository	PRIDE
AnnounceDate	2026-05-19
AnnouncementXML	Submission_2026-05-18_22:34:50.929.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yuki Maeda
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	ZenoTOF 7600

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-11 09:34:01	ID requested
⏵ 1	2026-05-18 22:34:51	announced

10.1007/s00401-026-03020-7;

Ono M, Kumagai Y, Hirata K, Maeda Y, Abe Y, Endo H, Shimizu H, Kakita A, Uchida Y, Takado Y, Altered astrocyte-neuron crosstalk in progressive supranuclear palsy: integrated evidence from proteomics and magnetic resonance spectroscopy. Acta Neuropathol, 151(1):(2026) [pubmed]

submitter keyword: LC-MSMS, PSP, SWATH,Progressive supranuclear palsy, Cingulate cortex

Yasuo Uchida
contact affiliation	Graduate school of Biomedical and Health Sciences, Hiroshima University
contact email	yuchida@hiroshima-u.ac.jp
lab head
Yuki Maeda
contact affiliation	Hiroshima University
contact email	yuki16270102@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD066064
     1. Label: PRIDE project
     2. Name: Disruption of astrocyte-neuron crosstalk in PSP: Integrated evidence from proteomics and MRS