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Manganese‐ and 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity display differences in morphological, electrophysiological and genome‐wide alterations: implications for idiopathic Parkinson's disease
Author(s) -
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
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14147
Subject(s) - dopaminergic , biology , neuroscience , parkinsonism , neurotoxicity , parkinson's disease , microbiology and biotechnology , medicine , dopamine , disease , toxicity
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 .