4af71fddd786cc187bafd977840c1223 ijms-26-11169.pdf 025e14c280c90512e3de467202368477f33640b6 ijms-26-11169.pdf 1693ccbfe6c19079ba92eaffd91109c2fcb40965369a4a5f425bc65286fe72b2 ijms-26-11169.pdf Title: Does Platelet Transcriptome Dysregulation Across the Lewy Body Continuum Mirror Neuronal Dysfunction? Subject: 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 -synucleinopathies. Keywords: platelet transcriptome; dementia with Lewy bodies; Parkinson’s disease; Alzheimer’s disease; idiopathic REM sleep behavior disorder; RNA sequencing; differential gene expression Author: Laura Arnaldo, Jorge Mena, David Adamuz, Alex Menéndez, Mònica Serradell, Daniela Samaniego, Carles Gaig, Lourdes Ispierto, Dolores Vilas, Alex Iranzo, Dag Aarsland, Pau Pastor and Katrin Beyer Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25; modified using OpenPDF 1.4.2 CreationDate: Wed Nov 19 11:07:14 2025 CET ModDate: Wed Nov 19 11:14:38 2025 CET Custom Metadata: yes Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 26 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3191124 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- CNQCWB+URWPalladioL-Bold Type 1 Custom yes yes yes 200 0 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2025-12-17 12:42:01 CET Size: 3191124 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 784 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Item: Title: Results Children: Item: Title: Demographic and Clinical Data Item: Title: Comparison of Gene Expression Profiles Across RNA-Seq Studies Children: Item: Title: CTRLs Item: Title: PD Item: Title: Classification of Transcripts Expressed in PLTs Children: Item: Title: Long-Non-Coding RNA (lncRNA) Item: Title: Minor RNAs Item: Title: Differential Gene Expression, Gene Ontology (GO) Enrichment and KEGG Pathway Analysis Item: Title: Discussion Children: Item: Title: Comparison of PLT RNA-Seq Studies Item: Title: The Composition of the PLT Transcriptome Item: Title: Deregulation of Gene Expression in PLTs Children: Item: Title: IRBD and DLB: Progressive Molecular Impairment and Shared Pathway Dysregulation Item: Title: PD and AD: Disease Heterogeneity Item: Title: Future Biomarker Development Item: Title: Materials and Methods Children: Item: Title: Source of PLT Samples Item: Title: PLT Obtaining and RNA Purification Item: Title: Total RNA Discovery by Next-Generation Sequencing (NGS) Item: Title: Sequencing Data Analysis Item: Title: Comparison of RNA Expression Between RNA-Seq Studies Item: Title: LncRNA and Minor RNA Distribution Analysis Item: Title: Gene Ontology (GO) Enrichment and KEGG Pathway Analysis Item: Title: Conclusions Item: Title: Appendix A Children: Item: Title: Item: Title: Item: Title: Item: Title: Appendix B Children: Item: Title: Item: Title: Item: Title: Item: Title: Item: Title: References Info: Title: Does Platelet Transcriptome Dysregulation Across the Lewy Body Continuum Mirror Neuronal Dysfunction? Author: Laura Arnaldo, Jorge Mena, David Adamuz, Alex Menéndez, Mònica Serradell, Daniela Samaniego, Carles Gaig, Lourdes Ispierto, Dolores Vilas, Alex Iranzo, Dag Aarsland, Pau Pastor and Katrin Beyer Subject: 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 -synucleinopathies. 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