SNCA locus Triplication Drives Severe Parkinson’s Disease: Platelet and Blood Expression Profiles Evidence Systemic Involvement
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Parkinson disease (PD) is increasingly recognized as a multisystem condition with substantial immune involvement. Functional parallels described between neurons and platelets have raised interest in the latter as a window into neurodegenerative disease mechanisms. While most PD cases are sporadic, rarely, mutations or gene dosage increases of SNCA cause familial PD. We report the case of the ninth PD patient carrying a SNCA locus triplication on chromosome 4q21.1 (SNCA3x), characterized by early-onset dementia and encompassing the largest number of coding genes described to date. To explore molecular correlates of disease progression, we longitudinally profiled the gene expression in blood and platelets from the SNCA3x PD patient in early and advanced stages, compared with healthy controls and early-onset PD patients stratified by age and sex. Early-stage PD was characterized by the downregulation of 14-3-3 and monoamine transporter genes, along with the upregulation of ribosomal genes in platelets, SPP1 tv1 in blood, and of inflammatory and PPM1K phosphatase genes in both blood and platelets. In the advanced stage of PD, we observed overexpression of SNCA and MMRN1 in blood and platelets. These dynamic shifts suggest a stage-dependent platelet signature that mirrors neurodegenerative and immune pathways. Our findings reveal shared molecular mechanisms with other forms of PD and underscore platelets as a peripheral source of biomarker discovery in PD.
