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

Abstract

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.

LPS Triggers Acute Neuroinflammation and Parkinsonism Involving NLRP3 Inflammasome Pathway and Mitochondrial CI Dysfunction in the Rat

“…Increasing evidence also supports the pathological role of NLRP3 inflammasome in neurodegeneration based on a mutual association with mitochondrial dysfunction [36,[49][50][51], which correlates with neurodegeneration in parkinsonian rats with α-synucleinopathy [52]. Accordingly, we have shown here that mitochondrial CI dysfunction and NLRP3 activation coincided in the early phase of LPS-induced neuroinflammation and with an increase in nitrosative/oxidative stress, as we previously demonstrated [29].…”

“…The mitochondrial CI activity was determined as reported elsewhere [52]. The tissue from an entire SN was homogenized in PBS pH 7.4 and subsequently centrifugated for 5 min at 2000 g. The supernatants were collected and used to perform the analyses.…”

Oxidative Stress in Age-Related Neurodegenerative Diseases: An Overview of Recent Tools and Findings

“…They found that these two parameters of oxidative stress, as well as mitochondrial complex I dysfunction, positively correlate with neurodegeneration in different brain areas with α-synucleinopathy, such as the substantia nigra pars compacta, the striatum, the hippocampus and the olfactory bulb. Based on in silico studies, they suggested the involvement of peroxisome proliferator-activated receptors (PPAR) alpha (PPAR-α) and gamma (PPAR-γ) in this process [98], since PPARs activation induces fatty acid oxidation (which, in turn, generates ROS) [99]. However, this mechanism needs to be further explored.…”

The neuroprotective effects of targeting key factors of neuronal cell death in neurodegenerative diseases: The role of ER stress, oxidative stress, and neuroinflammation

“…This will promote Cyt C release and caspase-9 activation, which leads to neuronal cell death and facilitating PD pathogenesis ( Figure 2 ; Lin and Beal, 2006 ). Defect in Complex I of the mitochondrial electron transport chain by aggregation of α-synuclein and PTEN-induced putative kinase 1 (PINK1) mutations can be also involved in PD pathogenesis by inducing neuronal apoptosis and failure in maintaining mitochondrial membrane potential, respectively (Liu et al, 2017 ; Morales-Martínez et al, 2022 ).…”