TNF-α regulates miRNA targeting mitochondrial complex-I and induces cell death in dopaminergic cells

Abstract

Parkinson's disease (PD) is a complex neurological disorder of the elderly population and majorly shows the selective loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) region of the brain. The mechanisms leading to increased cell death of DAergic neurons are not well understood. Tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine is elevated in blood, CSF and striatum region of the brain in PD patients. The increased level of TNF-α and its role in pathogenesis of PD are not well understood. In the current study, we investigated the role of TNF-α in the regulation of cell death and miRNA mediated mitochondrial functions using, DAergic cell line, SH-SY5Y (model of dopaminergic neuron degeneration akin to PD). The cells treated with low dose of TNF-α for prolonged period induce cell death which was rescued in the presence of zVAD.fmk, a caspase inhibitor and N-acetyl-cysteine (NAC), an antioxidant. TNF-α alters mitochondrial complex-I activity, decreases adenosine triphosphate (ATP) levels, increases reactive oxygen species levels and mitochondrial turnover through autophagy. TNF-α differentially regulates miRNA expression involved in pathogenesis of PD. Bioinformatics analysis revealed that the putative targets of altered miRNA included both pro/anti apoptotic genes and subunits of mitochondrial complex. The cells treated with TNF-α showed decreased level of nuclear encoded transcript of mitochondrial complexes, the target of miRNA. To our knowledge, the evidences in the current study demonstrated that TNF-α is a potential regulator of miRNAs which may regulate mitochondrial functions and neuronal cell death, having important implication in pathogenesis of PD.

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

“…mir155 is also found to be elevated in AD and to contribute to neuroninflammation in this disease [139] and identified as a biomarker [124,133]. In PD, miR155 has been implicated in mitochondrial regulation in dopaminergic cell death in later stage [140], however this study presents a link between miR155 and pre-motor PD for the first time.…”

The Differentially Expressed Circular RNAs in the Substantia Nigra and Corpus Striatum of Nrf2-Knockout Mice

“…MiR-27a was up-regulated in neuroepithelial cells with maternal diabetes-induced oxidative stress and played an inhibitory role on the expression of Nrf2 and Nrf2-controlled antioxidant genes [35]. Moreover, dysregulated miR-27a was found in neurodegenerative diseases including AD, HD and PD, as well [41][42][43]. MiR-34a was found to exert an inhibitory role on the Nrf2 pathway in a PD model and to be involved in the hepatoprotective effect of hydrogen sulphide on ischaemia/reperfusion injury [44,45] .…”

MicroRNA-709 Mediates Acute Tubular Injury through Effects on Mitochondrial Function

“…11,12 miRNAs normally bind to the 39-untranslated region (UTR) of target mRNA transcripts, resulting in translational silencing, translation inhibition, and/or mRNA degradation. [13][14][15] Recently, miRNAs, including miR-15b, miR -16, miR-195, and miR-424, have been found to modulate mitochondrial function in neurons and cancer cells [16][17][18] by targeting ADP-ribosylation factor-like 2 mRNA or mitochondrial OXPHOS, thereby regulating ATP production. In the kidney, miR-335 and miR-34a were reported to be regulators of mesangial cell senescence by targeting the mitochondria-localized genes SOD2 and thioredoxin reductase 2, 19 and miR-30e was shown to play a profibrotic role by targeting mitochondrial uncoupling protein 2.…”