ABSTRACT
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.
Subject(s)
1-Methyl-4-phenylpyridinium/toxicity , Dopaminergic Neurons/drug effects , Gene Expression Regulation/drug effects , Manganese/toxicity , Neurotoxins/toxicity , Action Potentials/drug effects , Animals , Apoptosis/drug effects , Behavior, Animal/drug effects , Cell Line, Transformed , Cell Survival/drug effects , DNA Methylation/drug effects , Dopaminergic Neurons/cytology , Dopaminergic Neurons/ultrastructure , L-Lactate Dehydrogenase/metabolism , Male , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Inbred C57BL , Neural Networks, Computer , Rats , Signal Transduction/drug effects , Transcriptome/drug effects , Transcriptome/physiology , Tyrosine 3-Monooxygenase/metabolismABSTRACT
Lethal Toxin Neutralizing Factor (LTNF) obtained from Opossum serum (Didephis virginiana) is known to exhibit toxin-neutralizing activity for envenomation caused by animals, plants and bacteria. Small synthetic peptide- LT10 (10mer) derived from N-terminal fraction of LTNF exhibit similar anti-lethal and anti-allergic property. In our in silico study, we identified Insulin Degrading Enzyme (IDE) as a potential target of LT10 peptide followed by molecular docking and molecular dynamic (MD) simulation studies which revealed relatively stable interaction of LT10 peptide with IDE. Moreover, their detailed interaction analyses dictate IDE-inhibitory interactions of LT10 peptide. This prediction of LT10 peptide as a novel putative IDE-inhibitor suggests its possible role in anti-diabetic treatment since IDE- inhibitors are known to assist treatment of Diabetes mellitus by enhancing insulin signalling. Furthermore, series of structure based peptidomimetics were designed from LT10 peptide and screened for their inhibitory interactions which ultimately led to a small set of peptidomimetic inhibitors of IDE. These peptidomimetic thus might provide a new class of IDE-inhibitors, those derived from LT10 peptide.
Subject(s)
Hypoglycemic Agents/chemistry , Insulysin/metabolism , Peptide Fragments/chemistry , Peptide Fragments/pharmacology , Peptidomimetics/chemistry , Animals , Diabetes Mellitus, Type 2 , Drug Design , Hypoglycemic Agents/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Opossums/metabolism , Peptidomimetics/pharmacology , Structure-Activity RelationshipABSTRACT
The enzyme aminopeptidase P (AP-P) is encountered in diverse vertebrate and invertebrate phyla and is known to act on proteins and peptides by releasing their N-terminal amino acid when the penultimate amino acid is proline. The present study is the first attempt at visualizing distribution of this polypeptide in the brain of a vertebrate species. The distribution of this enzyme was studied immunocytochemically in the forebrain of frog Microhyla ornata using antisera directed against cytosolic aminopeptidase P (DAP-P) of Drosophila melanogaster. Receptor cells in the olfactory epithelium exhibited strong AP-P like immunoreaction (ir). Immunoreactive fibers arising from the olfactory epithelium as well as vomeronasal organ joined the olfactory nerve, entered into the olfactory bulb, or accessory olfactory bulb and terminated in distinct glomerular formations. Some immunoreactive fibers traveled caudally and terminated in discrete areas in the telencephalon or diencephalon. Strong AP-P-ir was also seen in the cells of pars intermedia and pars distalis of the pituitary. The pattern of immunoreactivity suggests a role for AP-P in the processing of olfactory information and in hypophysial regulation.
