Neuronal Oxidative Stress Promotes α-Synuclein Aggregation In Vivo.
Neuronal Oxidative Stress Promotes α-Synuclein Aggregation In Vivo.
复制标题
DOI：
10.3390/antiox11122466
复制
发表时间：
2022-12-15
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
遗传和环境因素都会增加患帕金森病的风险。许多已知的遗传因素影响α-突触核蛋白的聚集或降解，而大多数已确定的环境因素产生氧化应激。使用体外方法的研究已经确定了氧化应激可以加速α-突触核蛋白聚集体形成的机制，但缺乏证据支持这些过程在大脑中长时间的重要性。为了评估这一问题，我们评估了三种转基因小鼠的大脑α-synuclein聚集：hSyn小鼠在神经元中过度表达人α-synuclein并自发产生α-synuclein聚集；EAAT3−/−小鼠，表现出半胱氨酸摄取神经元特异性损伤和由此产生的神经元选择性慢性氧化应激；双转基因hSyn/EAAT3−/−小鼠。磷酸化丝氨酸129 α-突触核蛋白的定量免疫组化和α-突触核蛋白近端结扎实验评估聚集形成。两种方法均表明，双转基因hSyn/EAAT3−/−小鼠在各脑区α-突触核蛋白聚集密度显著高于同窝hSyn小鼠。在EAAT3−/−小鼠株中观察到可忽略不计的聚集形成，这表明两种基因型之间存在协同作用而不是加性相互作用。在运动功能评估中观察到类似的结果模式：极测试和旋转测试。总之，这些观察结果表明，慢性、低级别神经元氧化应激促进体内α-突触核蛋白聚集体的形成。这一过程可能有助于环境诱导的氧化应激参与特发性帕金森病α-突触核蛋白病理的机制。
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.
登录
查看更多内容
DOI：
10.1126/science.aat8407
发表时间：
2018-11-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kam TI;Mao X;Park H;Chou SC;Karuppagounder SS;Umanah GE;Yun SP;Brahmachari S;Panicker N;Chen R;Andrabi SA;Qi C;Poirier GG;Pletnikova O;Troncoso JC;Bekris LM;Leverenz JB;Pantelyat A;Ko HS;Rosenthal LS;Dawson TM;Dawson VL
通讯作者：
Dawson VL
影响因子：
6.1
作者：
Anandhan, Annadurai;Rodriguez-Rocha, Humberto;Bohovych, Iryna;Griggs, Amy M.;Zavala-Flores, Laura;Reyes-Reyes, Elsa M.;Seravalli, Javier;Stanciu, Lia A.;Lee, Jaekwon;Rochet, Jean-Christophe;Khalimonchuk, Oleh;Franco, Rodrigo
通讯作者：
Franco, Rodrigo
影响因子：
5.4
作者：
Cook, Casey;Stetler, Caroline;Petrucelli, Leonard
通讯作者：
Petrucelli, Leonard
影响因子：
25
作者：
Aoyama, K;Suh, SW;Swanson, RA
通讯作者：
Swanson, RA
影响因子：
6.1
作者：
Klivenyi, P;Siwek, D;Beal, MF
通讯作者：
Beal, MF