​SEVERE PARKINSON'S DISEASE DRIVEN ​BY <EM>SNCA </EM>TRIPLICATION: ​PLATELET AND BLOOD ​EXPRESSION REVEAL SYSTEMIC INVOLVEMENT

Parkinson’s disease (PD) is increasingly understood as a multisystem disorder with significant immune involvement. Functional similarities between neurons and platelets have positioned platelets as a promising peripheral model for investigating neurodegenerative mechanisms. Although the majority of PD cases are sporadic, rare familial forms arise from mutations or increased gene dosage of the alpha-synuclein gene SNCA. Here, we present the ninth reported case of a PD patient harbouring a SNCA locus triplication on chromosome 4q21.1 (SNCA3x). The identified triplication is the largest coding-gene triplication described to date and, clinically, it is characterized by an aggressive disease course with early-onset dementia.
To investigate molecular correlates of disease progression, we performed longitudinal gene expression profiling in blood and platelets from the SNCA3x patient at early and advanced disease stages. Comparisons were made with healthy controls and age- and sex-matched early-onset PD patients. In the early stage, platelet analysis revealed downregulation of 14-3-3 and monoamine transporter genes, alongside upregulation of ribosomal genes, while blood showed increased expression of SPP1tv1. Both compartments displayed elevated inflammatory and PPM1K phosphatase gene expression. In advanced PD, SNCA and MMRN1 were overexpressed in blood and platelets.
These findings reveal dynamic, stage-dependent molecular signature in platelets that reflect neurodegenerative and immune-related pathways. Our results highlight shared molecular mechanisms across PD subtypes. Moreover, our results support the use of platelets as a peripheral source for biomarker discovery in PD, providing insight into both disease progression and potential therapeutic targets.