Low-Dose Radiation Effects on the Substantia Nigra in Swine: Insights into Parkinson’s Disease Biomarkers

Idiopathic Parkinson’s Disease (iPD) is a neurodegenerative disorder influenced by genetic and environmental factors, including ionizing radiation. While high-dose radiation (HDR) is linked to neuroinflammation and neuronal degeneration, the effects of low-dose radiation (LDR) remain unclear. This study examined the impact of acute total-body LDR (1.79 Gy) on the substantia nigra (SN) of swine, a large mammal model with strong neuroanatomical and neurophysiological similarities to humans. We analyzed key iPD markers, including α-synuclein (α-syn), phosphorylated α-syn (pα-syn), tyrosine hydroxylase (TH), and genetic-PD (LRRK2, GBA, VPS13C, Cathepsin D) related molecules. Neuroinflammation was assessed via GFAP levels, and mitochondrial alterations were evaluated through ATP5A, SDHB, and NDUF8 expression in radiation-exposed (RAD) vs. sham (SH) animals. Fourteen male Göttingen minipigs were divided into RAD (n=6) and SH (n=8) group. Protein expression was analyzed via Western blot (WB), while histological (hematoxylin and eosin [HE], Cresyl Violet [CV]) and immunohistochemistry (TH, GFAP) assessments examined potential neuronal and glial abnormalities in the SN. No significant differences were found between RAD and SH group in iPD-related markers examined. Lrrk2 was undetectable, consistent with its minimal SN expression in most mammals. All mitochondrial markers examined remained unchanged after LDR exposure, and histological/IHC analysis revealed no pathological tissue abnormalities, including vascular or peri-vascular lesions or neuronal/glial changes in RAD vs. SH swine SN. These findings suggest that a single acute total-body LDR (<2Gy) does not induce detectable short-term (4 weeks) changes in either iPD or genetic-PD related markers in the SN of a large animal (swine). However, further research is needed to explore whether chronic or cumulative LDR exposures could contribute to long-term PD-related molecular changes, if any. In general, this study provides new insights into the mostly unexplored hormetic effects of LDR on the central nervous system, particularly on the SN, in large mammals.