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

• Published in: International journal of molecular sciences 2022-09, Vol.23 (19), p.11394
• Main Authors: Morales-Martínez, Adriana, Martínez-Gómez, Paola A., Martinez-Fong, Daniel, Villegas-Rojas, Marcos M., Pérez-Severiano, Francisca, Del Toro-Colín, Miguel A., Delgado-Minjares, Karen M., Blanco-Alvarez, Víctor Manuel, Leon-Chavez, Bertha Alicia, Aparicio-Trejo, Omar Emiliano, Baéz-Cortés, Mauricio T., Cardenas-Aguayo, Maria-del-Carmen, Luna-Muñoz, José, Pacheco-Herrero, Mar, Angeles-López, Quetzalli D., Martínez-Dávila, Irma A., Salinas-Lara, Citlaltepetl, Romero-López, José Pablo, Sánchez-Garibay, Carlos, Méndez-Cruz, Adolfo R., Soto-Rojas, Luis O.
• Format: Article
• Language: English
• Subjects: Animal models; Brain; Cytoplasm; Electron transport chain; Mitochondria; NADH-ubiquinone oxidoreductase; Neostriatum; Neurodegeneration; Neurotoxicity; Olfactory bulb; Oxidative stress; Parkinson's disease; Peroxisome proliferator-activated receptors; Population; Substantia nigra; Synuclein; Therapeutic targets
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms231911394

The α-synucleinopathies constitute a subset of neurodegenerative disorders, of which Parkinson’s disease (PD) is the most common worldwide, characterized by the accumulation of misfolded α-synuclein in the cytoplasm of neurons, which spreads in a prion-like manner to anatomically interconnected brain areas. However, it is not clear how α-synucleinopathy triggers neurodegeneration. We recently developed a rat model through a single intranigral administration of the neurotoxic β-sitosterol β-D-glucoside (BSSG), which produces α-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 α-synucleinopathy (Substantia nigra pars compacta, the striatum, in the hippocampus and the olfactory bulb, where α-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-α) and gamma (PPAR-γ). These findings will contribute to elucidating the pathophysiological mechanisms associated with α-synucleinopathies and lead to the identification of new early biomarkers and therapeutic targets.