Oxidative Stress and Mitochondrial Complex I Dysfunction Correlate with Neurodegeneration in an alpha-Synucleinopathy Animal Model

The alpha-synucleinopathies constitute a subset of neurodegenerative disorders, of which Parkinson's disease (PD) is the most common worldwide, characterized by the accumulation of misfolded alpha-synuclein in the cytoplasm of neurons, which spreads in a prion-like manner to anatomically interconnected brain areas. However, it is not clear how alpha-synucleinopathy triggers neurodegeneration. We recently developed a rat model through a single intranigral administration of the neurotoxic beta-sitosterol beta-D-glucoside (BSSG), which produces alpha-synucleinopathy. In this model, we aimed to evaluate the temporal pattern of levels in oxidative and nitrosative stress and mitochondrial complex I (CI) dysfunction and how these biochemical parameters are associated with neurodegeneration in different brain areas with alpha-synucleinopathy (Substantia nigra pars compacta, the striatum, in the hippocampus and the olfactory bulb, where alpha-syn aggregation spreads). Interestingly, an increase in oxidative stress and mitochondrial CI dysfunction accompanied neurodegeneration in those brain regions. Furthermore, in silico analysis suggests a high-affinity binding site for BSSG with peroxisome proliferator-activated receptors (PPAR) alpha (PPAR-alpha) and gamma (PPAR-gamma). These findings will contribute to elucidating the pathophysiological mechanisms associated with alpha-synucleinopathies and lead to the identification of new early biomarkers and therapeutic targets.