Astrocytic HSP90AA1 Upregulation and Altered Synaptic Signaling in Parkinson's Disease: Transcriptomic Screening and In Vivo Validation.

Overview

1. Center for Neurological Diseases, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
2. Changsha Blood Center, Changsha 410024, China

Abstract

Parkinson’s disease (PD) is a multisystem disorder in which gastrointestinal dysfunction often precedes motor symptoms, yet the molecular links between peripheral stress and central neurodegeneration remain unclear. We investigated whether genes commonly dysregulated in PD and a classic model of intestinal inflammation (IBD) might reveal conserved stress-responsive molecules relevant to brain pathology. Shared gene signatures between PD and inflammatory bowel disease (IBD) were identified from peripheral blood transcriptomes using weighted gene co-expression network analysis (WGCNA). Hub genes were prioritized via protein–protein interaction (PPI) analysis and evaluated for expression consistency in independent brain tissue transcriptomic datasets. Single-cell RNA sequencing (scRNA-seq) of the PD substantia nigra was used to define the cellular context of the key hub gene, and CellChat analysis assessed intercellular communication changes. Immunofluorescence validation was performed in an MPTP-induced PD mouse model. We identified 79 shared genes and 6 hub genes, among which only HSP90AA1 showed consistent upregulation across independent PD transcriptomic validation datasets. Functional enrichment highlighted inflammation-related pathways. Because peripheral immune infiltration showed only minor changes, we further investigated the cellular context of HSP90AA1 within the PD brain. ScRNA-seq analysis of the PD substantia nigra demonstrated that HSP90AA1 was expressed across multiple cell populations. Integration with transcriptional regulatory analysis identified TP53 as a potential upstream regulator, and the strongest TP53–HSP90AA1 co-expression and cellular colocalization signals were observed in astrocytes, prompting further astrocyte-focused investigation. CellChat analysis revealed altered intercellular communication patterns in PD substantia nigra, including changes in synapse-associated ligand–receptor interaction signatures, particularly involving NCAM-related pathways. In the MPTP-induced PD mouse model, immunofluorescence identified astrocytic HSP90α upregulation, and increased nuclear p53 signal in astrocytes, accompanied by dopaminergic neuron loss. Conclusion: Astrocytic upregulation of HSP90AA1 is associated with altered synapse-related intercellular communication patterns in the PD substantia nigra, potentially involving a predicted TP53 associated regulatory component. These findings, validated in an MPTP mouse model, identify HSP90AA1 as a candidate stress-responsive hub linking peripheral inflammatory states with astrocyte-associated molecular alterations in PD, providing a framework for further experimental investigation.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE22491, at NCBI GEO; found in the text, “4.1. Data Selection”

Other data links

• ncbi.nlm.nih.gov/geo, NCBI; found in the text, “4.1. Data Selection”

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 5 keywords, 17 MeSH terms, 1 funder, 39 references.

Cite

This paper

Xu, Y., Shi, Y., Li, Y., Luo, J., & Jin, W.-N. (2026). Astrocytic HSP90AA1 Upregulation and Altered Synaptic Signaling in Parkinson's Disease: Transcriptomic Screening and In Vivo Validation. International journal of molecular sciences, 27(16), 7140. https://doi.org/10.3390/ijms27167140

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