GATD3A-mediated monocyte homeostasis and compartmentalized erythrocyte alpha-synuclein discriminate early Parkinson's...

Differentiating early-stage Parkinson's 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.

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.

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.

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.