Manganese and 1-methyl-4-phenylpyridinium (MPP(+) ) induced neurotoxicity indicate differences in morphological, electrophysiological and genome-wide alterations: Implications for idiopathic Parkinson’s disease.
J Neurochem. 2017 Aug 12;:
Authors: Mythri RB, Raghunath NR, Narwade SC, Pandareesh MD, Sabitha KR, Aiyaz M, Chand B, Sule M, Ghosh K, Kumar S, Shankarappa B, Soundararajan S, Alladi PA, Purushottam M, Gayathri N, Deobagkar DD, Laxmi TR, Muchukunte Mukunda SB
Idiopathic Parkinson’s disease (iPD) 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 PD toxin 1-methyl-4-phenylpyridinium ion (MPP(+) ) and manganese (Mn) followed by validation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 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 (0-5Hz). 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 (JAK-STAT) 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 JAK-STAT pathway. We conclude that iPD and atypical Parkinsonism have divergent neurotoxicological manifestation at the dopaminergic neuronal level with implications for pathobiology and evolution of novel therapeutics. This article is protected by copyright. All rights reserved.
PMID: 28801915 [PubMed – as supplied by publisher]
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