Brain region-specific and systemic transcriptomic alterations in a human alpha-synuclein overexpressing rat model

Synucleinopathies are age-dependent neurodegenerative diseases characterized by alpha-synuclein accumulation with distinct vulnerabilities across brain regions. Understanding early disease stages is essential to uncover initial molecular changes that might enable earlier diagnosis and causal therapy. In this study, we profiled longitudinal and brain region-resolved gene expression changes in a rat model of synucleinopathies overexpressing human <i>SNCA</i>. Transcriptomic analyses were performed on gene and transcript level of striatal, frontocortical, and cerebellar tissue in 5- and 12-month-old transgenic (BAC SNCA) and wild type rats revealing that <i>SNCA</i> overexpression leads to age-dependent transcriptomic changes that largely occur region-specific. In frontal cortex, dysregulation of myelination-associated genes agreed with Parkinson patient data as shown before. In addition, BAC SNCA rats displayed more gene expression changes at younger age, with a common and characteristic alteration pattern across all three examined brain regions. We also identified a cross-regional set of differential genes that were affected by <i>SNCA</i> overload. This set was also partially reflected in the gut transcriptome of the same rat model, suggesting a systemic impact of <i>SNCA</i> overload. Taken together, our findings highlight both brain region-specific vulnerabilities and global molecular perturbations associated with alpha-synuclein biology and provide insights into early transcriptomic changes in synucleinopathies.