Excess amounts of 3-iodo-L-tyrosine induce Parkinson-like features in heck tor experimental approaches of Parkinsonism
Excess amounts of 3-iodo-L-tyrosine induce Parkinson-like features in heck tor experimental approaches of Parkinsonism
复制标题
DOI：
10.1016/j.neuro.2018.06.002
复制
发表时间：
2018-07-01
期刊：
影响因子：
3.4
通讯作者：
Bis-Humbert, Cristian
中科院分区：
文献类型：
--
作者：
Fernandez-Espejo, Emilio;Bis-Humbert, Cristian
3-碘-l -酪氨酸可能在帕金森病中发挥作用，因为这种分子在高浓度下能够抑制酪氨酸-羟化酶活性，酪氨酸-羟化酶是多巴胺生物合成中的限速酶。3-碘-l -酪氨酸通过培养的黑质神经元、腹膜下注射后的空肠神经系统和单侧脑内注射后的黑质纹状体系统三种方法检测其可能的帕金森样效应。3-碘- l -酪氨酸是一种生理分子，其浓度高于人体血清水平。通过α -突触核蛋白和酪氨酸羟化酶的异常聚集、酪氨酸羟化酶表达和纹状体突起的神经元和纤维的缺失、酪氨酸羟化酶密度的降低以及帕金森样运动和非运动缺陷来评估帕金森样体征。脑模型采用氟金逆行示踪剂。研究结果显示，过量的3-碘-l -酪氨酸在三种实验方法中诱导帕金森样效应。因此，培养的黑质神经元显示，在3-碘- l -酪氨酸暴露后，胞浆内含有表达a-突触核蛋白和酪氨酸羟化酶的包涵体。腹腔内长期输注3-碘- l -酪氨酸导致α -突触核蛋白聚集，α -突触核蛋白阳性纤维变厚，空肠壁内神经丛和神经节中酪氨酸-羟化酶阳性细胞和纤维减少。向小鼠左背纹状体注入3-碘-l -酪氨酸会损害黑质纹状体系统，其表现为纹状体酪氨酸羟化酶密度降低，左侧黑质表达酪氨酸羟化酶和纹状体突起神经元数量减少，以及出现帕金森样行为缺陷，如运动障碍、运动迟缓、运动不平衡和运动方向偏倚。综上所述，过量的3-碘-l -酪氨酸在小鼠帕金森病的细胞、肠和脑途径中诱导帕金森样特征。
3-iodo-L-tyrosine might play a role in Parkinson's disease since this molecule is able, at high concentration, to inhibit tyrosine-hydroxylase activity, the rate-limiting enzyme in dopamine biosynthesis. The possible Parkinson-like effects of 3-iodo-L-tyrosine were tested on three experimental approaches in mice: cultured substantia nigra neurons, the enteric nervous system of the jejunum after infra-peritoneal infusions, and the nigrostriatal system following unilateral intrabrain injections. 3-iodo-L-tyrosine, a physiological molecule, was used at concentrations higher than its serum levels in humans. Parkinson-like signs were evaluated through abnormal aggregation of alpha-synuclein and tyrosine-hydroxylase, loss of tyrosine-hydroxylase-expressing and striatum-projecting neurons and fibers, reduced tyrosine-hydroxylase density, and Parkinson-like motor and non-motor deficits. The retrograde tracer FluoroGold was used in the brain model. The findings revealed that excess amounts of 3-iodo-L-tyrosine induce Parkinson-like effects in the three experimental approaches. Thus, culture neurons of substantia nigra show, after 3-iodo-L-tyrosine exposure, intracytoplasmic inclusions that express a-synuclein and tyrosine-hydroxylase. Intra-peritoneal infusions of 3-iodo-L-tyrosine cause, in the long-term, alpha-synuclein aggregation, thicker alpha-synuclein-positive fibers, and loss of tyrosine-hydroxylase-positive cells and fibers in intramural plexuses and ganglia of the jejunum. Infusion of 3-iodo-L-tyrosine into the left dorsal striata of mice damages the nigrostriatal system, as revealed through lower striatal tyrosine-hydroxylase density, reduced number of tyrosine-hydroxylase-expressing and striatum-projecting neurons in the left substantia nigra, as well as the emergence of Parkinson-like behavioral deficits such as akinesia, bradykinesia, motor disbalance, and locomotion directional bias. In conclusion, excess amounts of 3-iodo-L-tyrosine induce Parkinson-like features in cellular, enteric and brain approaches of Parkinsonism in mice.