Neuronal Oxidative Stress Promotes α-Synuclein Aggregation In Vivo

• Published in: Antioxidants 2022-12, Vol.11 (12), p.2466
• Main Authors: Won, Seok Joon, Fong, Rebecca, Butler, Nicholas, Sanchez, Jennifer, Zhang, Yiguan, Wong, Candance, Tambou Nzoutchoum, Olive, Huynh, Annie, Pan, June, Swanson, Raymond A
• Format: Article
• Language: English
• Subjects: aggregate; Aggregates; Antibodies; cysteine; Data analysis; Environmental factors; Experiments; Genetic factors; Genotype & phenotype; Genotypes; Immunohistochemistry; Kinases; Movement disorders; Neurodegenerative diseases; Observations; Oxidative stress; Parkinson's disease; Phosphoserine; Proteins; proximity ligation assay; Software; Synuclein; Transgenic mice; α-synuclein
• ISSN: 2076-3921; 2076-3921
• DOI: 10.3390/antiox11122466

Both genetic and environmental factors increase risk for Parkinson's disease. Many of the known genetic factors influence α-synuclein aggregation or degradation, whereas most of the identified environmental factors produce oxidative stress. Studies using in vitro approaches have identified mechanisms by which oxidative stress can accelerate the formation of α-synuclein aggregates, but there is a paucity of evidence supporting the importance of these processes over extended time periods in brain. To assess this issue, we evaluated α-synuclein aggregates in brains of three transgenic mouse strains: hSyn mice, which overexpress human α-synuclein in neurons and spontaneously develop α-synuclein aggregates; EAAT3 mice, which exhibit a neuron-specific impairment in cysteine uptake and resultant neuron-selective chronic oxidative stress; and double-transgenic hSyn/EAAT3 mice. Aggregate formation was evaluated by quantitative immunohistochemistry for phosphoserine 129 α-synuclein and by an α-synuclein proximity ligation assay. Both methods showed that the double transgenic hSyn/EAAT3 mice exhibited a significantly higher α-synuclein aggregate density than littermate hSyn mice in each brain region examined. Negligible aggregate formation was observed in the EAAT3 mouse strain, suggesting a synergistic rather than additive interaction between the two genotypes. A similar pattern of results was observed in assessments of motor function: the pole test and rotarod test. Together, these observations indicate that chronic, low-grade neuronal oxidative stress promotes α-synuclein aggregate formation in vivo. This process may contribute to the mechanism by which environmentally induced oxidative stress contributes to α-synuclein pathology in idiopathic Parkinson's disease.