Manganese‐ and 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity display differences in morphological, electrophysiological and genome‐wide alterations: implications for idiopathic Parkinson's disease

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.

Inhibition of mitochondrial complex II in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration

“…We investigated whether CII inhibitor triggers pathways that are different from CI inhibitor vs. metal toxin in neurons. This has implications for movement disorders and neurodegeneration as indicated in our previous study on Mn and MPP + models 21 . Since the concentration of the three toxins are varied, it is challenging to emphatically state that the differences between CII and CI events are not influenced by dose-dependent effects of the toxin.…”

“…Mitochondrial complex II assay was assessed as described 84,85 . Mitochondrial membrane potential was estimated using JC1 fluorescent dye as described 21 in control and 3-NPA treated N27 cells.…”

“…Whole genome microarray. Whole genome cDNA microarray was performed on control and 3-NPA treated cells as described 21 . N27 cell pellets were harvested and preserved in RNA-later (Thermo Fischer Scientific).…”

“…Pre-designed qPCR primers (KiCQ start primers, Sigma-Aldrich) were used along with SyBR green chemistry (Thermo Fisher Scientific) to analyze gene expression. Gene expression was normalized to GAPDH and expressed as fold change (2 −ΔΔCt ) with respect to control 21,92 .…”

Mitochondrial dysfunction in human skeletal muscle biopsies of lipid storage disorder

“…Recently, we observed that inhibitors of mitochondrial respiratory complexes not only influenced the mitochondrial function but also the nuclear genome (Mythri et al . and Ranganayaki et al ., unpublished). Interestingly, the global transcriptomic changes induced by an inhibitor of CI (1‐methyl‐4‐phenylpyridinium iodide) were significantly different from those induced by a CII inhibitor (3‐nitropropionic acid) and a non‐mitochondrial toxin (Manganese).…”