Abstract
Increasing evidence suggests that cross talk between α-synuclein pathology formation and mitochondrial dysfunction plays a central role in the pathogenesis of Parkinson's disease (PD) and related synucleinopathies. While mitochondrial dysfunction is a well-studied phenomenon in the substantia nigra, which is selectively vulnerable in PD and some models thereof, less information is available in other brain regions that are also affected by synuclein pathology. Therefore, we sought to test the hypothesis that early α-synuclein pathology causes mitochondrial dysfunction and that this effect might be exacerbated in conditions of increased vulnerability in affected brain regions, such as the amygdala. We combined a model of intracerebral α-synuclein pathology seeding with chronic glucocorticoid treatment, which models non-motor symptoms of PD and affects amygdala physiology. We measured mitochondrial respiration, reactive oxygen species (ROS) generation and protein abundance as well as α-synuclein pathology in male mice. Chronic corticosterone administration induced mitochondrial hyperactivity in the amygdala. Although injection of α-synuclein preformed fibrils (PFFs) into the striatum resulted in pronounced α-synuclein pathology in both striatum and amygdala, mitochondrial respiration in these brain regions was not compromised, regardless of corticosterone treatment. Our results suggest that early stage α-synuclein pathology does not influence mitochondrial respiration in the striatum and amygdala, even in corticosterone-induced respirational hyperactivity. We discuss our findings in light of relevant literature, warn of a potential publication bias and encourage scientists to report their negative results within the framework of this model.