Does Platelet Transcriptome Dysregulation Across the Lewy Body Continuum Mirror Neuronal Dysfunction?

Platelets are increasingly recognized as multifunctional cells with roles extending beyond hemostasis to immune regulation, inflammation, and neurodegeneration. Here, we performed RNA-Seq profiling of platelets from patients with idiopathic REM sleep behavior disorder (IRBD), dementia with Lewy bodies (DLB), Parkinson disease (PD), Alzheimer disease (AD), and healthy controls (CTRLs) to explore disease-specific transcriptomic signatures. Across all groups, the RNA class distribution was similar, dominated by mRNAs (78-80%) and long non-coding RNAs (lncRNAs; 15-16%). DLB platelets displayed a reduced proportion of lncRNAs, suggesting an impaired RNA regulation, whereas IRBD concentrated the highest number of disease-specific lncRNAs, half of which were Y-linked, consistent with the male predominance observed in alpha-synucleinopathies. Differential expression analysis (DEA) revealed extensive transcriptomic remodeling in IRBD and DLB, particularly affecting RNA processing, cytoskeletal organization, and platelet activation pathways, while PD and AD showed minimal changes. These findings suggest a progressive impairment of platelet activation and signaling across the DLB continuum, potentially mirroring neuronal dysfunction. The limited transcriptional deregulation in PD may reflect its pronounced biological heterogeneity, consistent with recent multidimensional disease models. Overall, our study highlights platelets as accessible indicators of early and disease-stage-specific molecular alterations in α-synucleinopathies.