Comparative analysis of 1-methyl-4-phenylpyridinium (MPP+) and manganese induced neurotoxic effects on DNA methylation in dopaminergic neurons

ABSTRACT: 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 L-DOPA differentiate both, the differences at the neuronal level are largely unknown. We investigated the morphological, physiological and molecular differences in dopaminergic neurons exposed to the PD toxin 1-methyl-4-phenylpyridinium ion (MPP+) and manganese (Mn). While Mn was neurotoxic at lower dose, MPP+ toxicity entailed oxidative damage, mitochondria dysfunction and glycolytic shift. Morphological analysis highlighted mitochondrial damage, while morphometric analysis indicated loss of neuronal processes in the MPP+ model and not in the Mn model. Elecrophysiological analysis demonstrated lower number of spikes and firing frequency in MPP+ treated cells, while it was unchanged in the Mn model. High throughput transcriptomic analysis revealed upregulation 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 and mitochondrial function, apoptosis and nuclear function, synaptic plasticity, neurotransmission and cytoskeletal architecture. Analysis of the JAK-STAT pathway with implications for neuritogenesis, neuronal proliferation and nuclear function revealed contrasting profile between Mn and MPP+ models. Genome-wide DNA methylation profile revealed significant differences between both models and substantiated the epigenetic basis of the difference in the JAK-STAT pathway. We conclude that iPD and atypical Parkinsonism represent a divergent neurotoxicological manifestation at the dopaminergic neuronal level with implications for pathobiology and to evolve novel therapeutics

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE92691 | GEO | 2017/10/04

SECONDARY ACCESSION(S): PRJNA358380

REPOSITORIES: GEO