"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."
BUFFALO, NY — November 3, 2025 — A new research paper featured on the cover of Volume 17, Issue 10 of Aging-US was published on October 20, 2025, titled " Brain region-specific and systemic transcriptomic alterations in a human alpha-synuclein overexpressing rat model ."
In this study, led by first author Vivien Hoof and corresponding author Thomas Hentrich from Saarland University , Germany, researchers investigated how excess alpha-synuclein—a protein linked to Parkinson's disease—affects gene activity in different brain regions and the gut. They found that early, region-specific gene disruptions may contribute to the appearance of disease, with some effects also detected in the gut. These early molecular changes could serve as biomarkers for Parkinson's and point to new directions for treatment.
Alpha-synuclein accumulates in the brains of individuals with Parkinson's disease and other age-related neurological conditions known as synucleinopathies. To better understand this process, the research team used a genetically modified rat model that overexpresses human alpha-synuclein. They studied gene expression in the striatum, cortex, and cerebellum—three key brain regions involved in movement and cognition—and analyzed how these changes evolved with age.
"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 […]"
The results showed that gene alterations appeared earlier and were more pronounced in young rats, particularly in the striatum and cortex, before any visible signs of disease manifested. This early disruption challenges the common belief that gene alterations gradually increase with age and suggests that early-life molecular changes may be critical in disease development.
The researchers also found that many gene expression changes were unique to individual brain regions. However, they identified a set of genes that were consistently affected across all brain regions and the gut. This suggests that the disease may begin to affect the entire body—not just the brain—long before symptoms become noticeable.
Several of the shared genes are involved in synaptic signaling and inflammation—processes known to be altered in Parkinson's. Others are linked to dopamine production and neuronal plasticity, indicating potential early efforts by the brain to compensate for the harmful effects of the alpha-synuclein buildup.
Overall, this study provides a detailed view of how alpha-synuclein affects gene networks early in the disease process. Understanding these changes may help identify biomarkers and develop targeted therapies before irreversible brain damage occurs.
Read the full paper: DOI: https://doi.org/10.18632/aging.206331
