Objective: To compare the neurotoxicological hallmarks induced by inhibitors of mitochondrial complex I (CI- 1- methyl-4- phenylpyridinium; MPP+), complex II (CII- 3- nitropropionic acid; 3- NPA) and a non- mitochondrial toxin (Manganese) with implications for neurodegenerative disorders (NDDs) including Parkinson’s disease (PD), Huntington’s disease (HD) and atypical PD (Manganism) respectively.

Background: Neurodegeneration manifesting as movement disorders share overlapping anatomical and biochemical networks that are compromised during the disease. Most of the degenerative changes have multifactorial etiology, all converging at mitochondrial dysfunction. Inhibition of mitochondrial complex activity is reported in PD and HD, but the neurotoxicological hallmarks induced by neurotoxins inhibiting these complexes remain unknown. Further, epigenetic mechanisms governing degenerative pathways in these diseases remain unclear.

Method: N27 neuronal cells treated with MPP+, 3- NPA and Mn at their LC50 concentrations were subjected to whole genome transcriptomics. Bioinformatics analysis established common/ exclusive networks regulated by the toxins, which were validated by immunoblotting and qRT- PCR.  Biochemical, ultrastructural and epigenetic methods were employed to assess the down-stream events following toxin exposure.

Results: Transcriptomics data revealed differential regulation of genes across the genome, which were significantly different among the treatment groups. Gene ontology analysis showed autophagy as one of the prominent players exclusively in the 3- NPA model. Further analysis from qRT- PCR and immunoblotting revealed growth factor mediated regulation of autophagy via the mTORC2 pathway in the 3-NPA model. Epigenetic profiling by assessment of histone acetylation signature showed a significant increase in acetylation of H3K56 and H4K5 that was unique to 3- NPA treatment. ChIP- seq analysis with H3K56Ac upon 3- NPA treatment correlated with the transcriptomics data with significant acetylation in genes associated with autophagy.

Conclusion: Movement disorders show unique transcriptomic and epigenetic signature at the neuronal level, thereby highlighting the toxin-specific molecular mechanisms and their influence on the degenerative changes observed in various NDDs.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/inhibition-of-mitochondrial-complexes-induces-unique-transcriptomic-and-epigenetic-profiles-implications-to-neurodegeneration-induced-movement-disorders/