{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T18:02:03Z","timestamp":1784570523544,"version":"3.55.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Differentiating early-stage Parkinson\u2019s disease (PD) from the parkinsonian variant of multiple system atrophy (MSA-P) remains a significant challenge due to overlapping clinical phenotypes. This study aimed to identify novel, minimally invasive biomarkers by integrating high-resolution peripheral monocyte transcriptomics with erythrocytic alpha-synuclein (alpha-Syn) distribution patterns.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We recruited 149 participants (75 PD and 74 MSA-P) to evaluate clinical features and composite peripheral inflammatory indices. To resolve subtle immune heterogeneity often masked in bulk blood analysis, single-cell RNA sequencing (scRNA-seq) was performed on peripheral blood mononuclear cells (PBMCs) from early-stage patients, followed by Quantitative Real-Time PCR (qRT-PCR) validation. Additionally, immunofluorescence was utilized to characterize the subcellular compartmentalization of alpha-Syn forms in erythrocytes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>While MSA-P patients exhibited more rapid progression and severe autonomic failure, standard inflammatory markers (e.g., NLR, MLR) failed to distinguish PD from MSA-P in the early clinical stages. However, scRNA-seq revealed distinct monocyte landscapes. Early MSA-P monocytes displayed an aggressive pro-inflammatory profile driven by chemokine upregulation (CXCL10, CXCL5), interferon pathway activation (IFI27). Conversely, early-stage PD monocytes exhibited a profile of precise homeostatic regulation and protective mitochondrial adaptation, characterized by significant GATD3A downregulation verified by qRT-PCR. Furthermore, distinct pathological patterns were identified: oligomeric alpha-Syn was predominantly sequestered on erythrocyte membranes in MSA-P, whereas pS129 alpha-Syn localized primarily to the cytoplasm in PD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study uncovers a divergent peripheral immune landscape where GATD3A-mediated monocyte homeostasis distinguishes early PD from the chemokine-driven inflammation and intense oxidative stress of MSA-P. Combined with distinct erythrocytic alpha-Syn membrane distribution patterns, these signatures offer a promising multidimensional strategy for the early differential diagnosis of these synucleinopathies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1818028","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T04:23:32Z","timestamp":1783571012000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["GATD3A-mediated monocyte homeostasis and compartmentalized erythrocyte alpha-synuclein discriminate early Parkinson\u2019s disease from MSA-P"],"prefix":"10.3389","volume":"17","author":[{"given":"Ying","family":"Jiang","sequence":"first","affiliation":[{"name":"Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"China National Clinical Research Center for Neurological 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