Pronounced α-synuclein pathology in a seeding-based mouse model is not sufficient to induce mitochondrial respiration deficits in the striatum and amygdala

Abstract

Increasing evidence suggests that crosstalk between -synuclein pathology formation and mitochondrial dysfunctions plays a central role in the pathogenesis of Parkinsons disease and related synucleinopathies. While mitochondrial dysfunction is a well-studied phenomenon in the substantia nigra, which is selectively vulnerable in Parkinsons disease 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 -synuclein pathology causes mitochondrial dysfunction, and that this effect might be exacerbated in conditions of increased vulnerability of affected brain regions, such as the amygdala. We combined a model of intracerebral -synuclein pathology seeding with chronic glucocorticoid treatment modelling non-motor symptoms of Parkinsons disease and affecting amygdala physiology. We measured mitochondrial respiration, ROS generation and protein abundance as well as -synuclein pathology in male mice. Chronic corticosterone administration induced mitochondrial hyperactivity in the amygdala. Although injection of -synuclein preformed fibrils into the striatum resulted in pronounced -synuclein pathology in both striatum and amygdala, mitochondrial respiration in these brain regions was altered in neither chronic corticosterone nor control conditions. Our results suggest that early stage -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 scientist to report their negative results in the frame of this model. Significance statementWe provide evidence that early stage synucleinopathy by itself or in combination with exogenous corticosterone induced amygdala hyperactivity did not compromise mitochondrial respiration in the striatum and amygdala in one of the most commonly used models of synucleinopathies. These results may explain, why this model in the hands of many research groups does not elicit pronounced Parkinsons disease like symptoms in the absence of mitochondrial dysfunction in brain regions strongly affected by synuclein pathology and involved in non-motor (amygdala) and motor (striatum) symptoms. Our findings call for rigorous investigation of the short- and long-term effects of -synuclein pathology on mitochondrial function/dysfunction in this model, in particular in brain regions strongly affected by neurodegeneration such as the substantia nigra pars compacta.