{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T19:53:06Z","timestamp":1793303586400,"version":"4.5.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Parkinson\u2019s disease (PD) is classically defined by dopaminergic neurodegeneration in the substantia nigra, yet how immune activation is linked to neurovascular dysfunction in the diseased brain remains incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Here, we integrated bulk substantia nigra microarray expression datasets with single-cell and spatial transcriptomic data to delineate disease-associated neurovascular and immune-related transcriptomic programs in PD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Across three independent human microarray cohorts, differential expression and weighted gene co-expression network analyses identified PD-associated genes enriched for synaptic processes together with immune, adhesion, and vascular-related pathways. Network topology analysis and machine-learning feature selection prioritized a five-gene candidate panel, among which NOTCH1 showed the most consistent cross-dataset association and external directional support. Importantly, quantitative real-time PCR (qRT-PCR) validation in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice further supported dysregulated Notch1 expression. Single-cell mapping placed NOTCH1 expression within neurovascular and glial cellular contexts, including pericytes and endothelial cells, while CellChat and NicheNet analyses nominated transcriptome-derived ligand-receptor relationships involving NOTCH-related, vascular, inflammatory, extracellular-matrix, and growth-factor-associated programs. Spatial transcriptomics from mouse 6-hydroxydopamine (6-OHDA) substantia nigra sections provided model-based anatomical context for spatial proximity between pericyte and microglial signatures, without establishing direct functional communication. In parallel, exploratory in silico perturbation and docking-based screening generated hypotheses regarding the NOTCH1-associated regulatory context and compounds with predicted docking affinity toward NOTCH1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Collectively, these analyses prioritize NOTCH1 as a reproducible PD-associated candidate gene and suggest that NOTCH1-related signals may be embedded within broader neurovascular, glial, inflammatory, extracellular-matrix, and immune-associated transcriptomic alterations. These findings provide a computational prioritization framework for future experimental validation rather than evidence of a defined NOTCH-driven mechanism.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2026.1862571","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T05:35:34Z","timestamp":1782970534000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrated bulk, single-cell, and spatial transcriptomic analyses prioritize NOTCH1 as a candidate gene associated with neurovascular and immune-related alterations in Parkinson\u2019s disease"],"prefix":"10.3389","volume":"20","author":[{"given":"Wenkui","family":"Li","sequence":"first","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Laboratory Center of Chongqing Medical University","place":["Chongqing, China"]},{"name":"Department of Neurology, Chongqing University Three Gorges Hospital","place":["Chongqing, China"]},{"name":"School of Medicine, Chongqing University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahao","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Laboratory Center of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changhong","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Laboratory Center of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Laboratory Center of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lifen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Laboratory Center of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"12379","DOI":"10.3390\/ijms252212379","article-title":"Parkinson's disease: biomarkers for diagnosis and disease progression","volume":"25","author":"Arya","year":"2024","journal-title":"Int. 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