title: 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.
authors.affiliation: Department of Cell Biology, School of Biological Sciences and Biotechnology, Indian Institute of Advanced Research (IIAR), Koba Institutional Area, Gandhinagar 382007, Gujarat, India; Department of Biochemistry, Faculty of Science, The M. S. University of Baroda, Vadodara 390002, Gujarat, India.
authors.forename: Paresh
authors.initials: P
authors.lastname: Prajapati
authors.affiliation: Department of Cell Biology, School of Biological Sciences and Biotechnology, Indian Institute of Advanced Research (IIAR), Koba Institutional Area, Gandhinagar 382007, Gujarat, India; Department of Biochemistry, Faculty of Science, The M. S. University of Baroda, Vadodara 390002, Gujarat, India.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Sripada
authors.affiliation: Department of Cell Biology, School of Biological Sciences and Biotechnology, Indian Institute of Advanced Research (IIAR), Koba Institutional Area, Gandhinagar 382007, Gujarat, India; Department of Biochemistry, Faculty of Science, The M. S. University of Baroda, Vadodara 390002, Gujarat, India.
authors.forename: Kritarth
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Cell Biology, School of Biological Sciences and Biotechnology, Indian Institute of Advanced Research (IIAR), Koba Institutional Area, Gandhinagar 382007, Gujarat, India; Department of Biochemistry, Faculty of Science, The M. S. University of Baroda, Vadodara 390002, Gujarat, India.
authors.forename: Khyati
authors.initials: K
authors.lastname: Bhatelia
authors.affiliation: Department of Cell Biology, School of Biological Sciences and Biotechnology, Indian Institute of Advanced Research (IIAR), Koba Institutional Area, Gandhinagar 382007, Gujarat, India.
authors.forename: Rochika
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Biochemistry, Faculty of Science, The M. S. University of Baroda, Vadodara 390002, Gujarat, India. Electronic address: singhraj1975@gmail.com.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Singh
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000201:enzymology* / Q000473:pathology; D042967:Electron Transport Complex I / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D010300:Parkinson Disease / Q000201:enzymology* / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D016166:Free Radical Scavengers; D035683:MicroRNAs; D011480:Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; C484771:benzyloxycarbonyl-valyl-aspartic acid fluoromethyl ketone; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I; D000111:Acetylcysteine
keywords: Inflammation; Mitochondria; Parkinson's disease; TNF-α; miRNA