Mythri Rajeswara Babu, Raghunath Narayana Reddy, Narwade Santosh Chandrakant, Pandareesh Mirazkar Dasharatha Rao, Sabitha Kollarkandi Rajesh, Aiyaz Mohamad, Chand Bipin, Sule Manas, Ghosh Krittika, Kumar Senthil, Shankarappa Bhagyalakshmi, Soundararajan Soundarya, Alladi Phalguni Anand, Purushottam Meera, Gayathri Narayanappa, Deobagkar Deepti Dileep, Laxmi Thenkanidiyoor Rao, Srinivas Bharath Muchukunte Mukunda
Department of Neurochemistry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, Karnataka, India.
Neurotoxicology Laboratory-Neurobiology Research Center, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, Karnataka, India.
J Neurochem. 2017 Nov;143(3):334-358. doi: 10.1111/jnc.14147. Epub 2017 Oct 3.
Idiopathic Parkinson's disease and manganese-induced atypical parkinsonism are characterized by movement disorder and nigrostriatal pathology. Although clinical features, brain region involved and responsiveness to levodopa distinguish both, differences at the neuronal level are largely unknown. We studied the morphological, neurophysiological and molecular differences in dopaminergic neurons exposed to the Parkinson's disease toxin 1-methyl-4-phenylpyridinium ion (MPP ) and manganese (Mn), followed by validation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and Mn mouse models. Morphological analysis highlighted loss of neuronal processes in the MPP and not the Mn model. Cellular network dynamics of dopaminergic neurons characterized by spike frequency and inter-spike intervals indicated major neuronal population (~ 93%) with slow discharge rates (0-5 Hz). While MPP exposure suppressed the firing of these neurons, Mn neither suppressed nor elevated the neuronal activity. High-throughput transcriptomic analysis revealed up-regulation of 694 and 603 genes and down-regulation of 428 and 255 genes in the MPP and Mn models respectively. Many differentially expressed genes were unique to either models and contributed to neuroinflammation, metabolic/mitochondrial function, apoptosis and nuclear function, synaptic plasticity, neurotransmission and cytoskeleton. Analysis of the Janus kinase-signal transducer and activator of transcription pathway with implications for neuritogenesis and neuronal proliferation revealed contrasting profile in both models. Genome-wide DNA methylomics revealed differences between both models and substantiated the epigenetic basis of the difference in the Janus kinase-signal transducer and activator of transcription pathway. We conclude that idiopathic Parkinson's disease and atypical parkinsonism have divergent neurotoxicological manifestation at the dopaminergic neuronal level with implications for pathobiology and evolution of novel therapeutics. Cover Image for this issue: doi. 10.1111/jnc.13821.
特发性帕金森病和锰诱导的非典型帕金森综合征的特征是运动障碍和黑质纹状体病变。尽管临床特征、受累脑区以及对左旋多巴的反应性可区分这两种疾病，但在神经元水平上的差异在很大程度上尚不清楚。我们研究了暴露于帕金森病毒素1-甲基-4-苯基吡啶离子（MPP⁺）和锰（Mn）的多巴胺能神经元的形态、神经生理和分子差异，随后在1-甲基-4-苯基-1,2,3,6-四氢吡啶和锰小鼠模型中进行了验证。形态学分析突出了MPP⁺模型中神经元突起的丧失，而锰模型中则没有。以放电频率和峰间间隔为特征的多巴胺能神经元的细胞网络动力学表明，主要神经元群体（约93%）放电速率缓慢（0-5Hz）。虽然MPP⁺暴露抑制了这些神经元的放电，但锰既没有抑制也没有提高神经元的活性。高通量转录组分析显示，在MPP⁺和锰模型中分别有694个和603个基因上调，428个和255个基因下调。许多差异表达基因在两种模型中是独特的，并且与神经炎症、代谢/线粒体功能、细胞凋亡和核功能、突触可塑性、神经传递和细胞骨架有关。对与神经突发生和神经元增殖相关的Janus激酶-信号转导子和转录激活子通路的分析显示，两种模型中的情况截然不同。全基因组DNA甲基化分析揭示了两种模型之间的差异，并证实了Janus激酶-信号转导子和转录激活子通路差异的表观遗传基础。我们得出结论，特发性帕金森病和非典型帕金森综合征在多巴胺能神经元水平上具有不同的神经毒理学表现，这对病理生物学和新型治疗方法的发展具有重要意义。本期封面图片：doi. 10.1111/jnc.13821。
