Chronic corticosterone enhancement aggravates alpha-synuclein brain spreading pathology and substantia nigra neurodegeneration in mice

Chronic stress and associated heightened glucocorticoid levels are risk factors for depression, a common non-motor symptom in Parkinson’s disease (PD). However, how heightened glucocorticoids influence PD neuropathology [alpha-synuclein (α-Syn) containing Lewy pathology and neurodegeneration] and disease progression is unclear. To address this knowledge gap, we investigated the impact of chronic corticosterone administration on α-Syn pathology, neurodegeneration, behavior and mitochondrial function in a mouse model of α-Syn pathology spreading after intracerebral injection of α-Syn preformed fibrils (PFFs). Our results demonstrate that heightened corticosterone aggravates neurodegeneration and α-Syn pathology spreading, intriguingly to specific brain regions, such as the entorhinal cortex. Corticosterone-treatment abolished distinct physiological adaptations after PFF-injection and induced differential physiological and behavioral consequences. Taken together, our work points to elevated glucocorticoids as a risk factor for the development of the neuropathological hallmarks of PD. Strategies aimed at reducing glucocorticoid levels might slow down pathology spreading and disease progression in synucleinopathy.