Browsing by Author "O'Donnell, Janis M."
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Item Catecholamines up integrates dopamine synthesis and synaptic trafficking(Wiley, 2011) Wang, Zhe; Ferdousy, Faiza; Lawal, Hakeem; Huang, Zhinong; Daigle, J. Gavin; Izevbaye, Iyare; Doherty, Olugbenga; Thomas, Jerrad; Stathakis, Dean G.; O'Donnell, Janis M.; University of Alabama Tuscaloosa; University of Mississippi Medical Center; University of Mississippi; University of VirginiaThe highly reactive nature of dopamine renders dopaminergic neurons vulnerable to oxidative damage. We recently demonstrated that loss-of-function mutations in the Drosophila gene Catecholamines up (Catsup) elevate dopamine pools but, paradoxically, also confer resistance to paraquat, an herbicide that induces oxidative stress-mediated toxicity in dopaminergic neurons. We now report a novel association of the membrane protein, Catsup, with GTP cyclohydrolase rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis and tyrosine hydroxylase, rate-limiting enzyme for dopamine biosynthesis, which requires BH4 as a cofactor. Loss-of-function Catsup mutations cause dominant hyperactivation of both enzymes. Elevated dopamine levels in Catsup mutants coincide with several distinct characteristics, including hypermobility, minimal basal levels of 3,4-dihydroxy-phenylacetic acid, an oxidative metabolite of dopamine, and resistance to the vesicular monoamine transporter inhibitor, reserpine, suggesting that excess dopamine is synaptically active and that Catsup functions in the regulation of synaptic vesicle loading and release of dopamine. We conclude that Catsup regulates and links the dopamine synthesis and transport networks.Item Disruption of dopamine homeostasis has sexually dimorphic effects on senescence characteristics of Drosophila melanogaster(Wiley, 2017) Bednarova, Andrea; Hanna, Marley E.; Rakshit, Kuntol; O'Donnell, Janis M.; Krishnan, Natraj; Mississippi State University; Czech Academy of Sciences; Biology Centre of the Czech Academy of Sciences; Mayo Clinic; University of Alabama Tuscaloosa; Arkansas State UniversityThe neurotransmitter dopamine (DA) is known to be involved in a multitude of physiological processes. We investigated sexually dimorphic effects of disruptions in DA homeostasis and its relationship to senescence using three different Drosophila melanogaster mutants namely Catsup (Catsup(26)) with elevated DA levels, and pale (ple(2)), Punch (Pu-Z22) with depleted DA levels. In all genotypes including controls, DA levels were significantly lower in old (45-50-day-old) flies compared with young (3-5-day-old) in both sexes. Interestingly, females had lower DA content than males at young age whereas this difference was not observed in old age, suggesting that males had a larger decline in DA levels with age. Females, in general, were longer lived compared with males in all genotypes except ple(2) mutants with depleted DA levels. This phenotype was abolished in the ple(2) rescue flies. Interestingly, females also demonstrated marked age-related decline in circadian locomotor activity compared with males. Old Catsup 26 males with elevated DA levels accumulated significantly lower levels of lipid peroxidation product 4-hydroxy 2-nonenal (4-HNE) compared with age-matched wild type, ple(2) and Pu-Z22 mutant males. In Catsup 26 revertant lines this phenomenon was absent. We also observed a sexually dimorphic response in the expression levels of key stress and aging associated and/or related transcription factor genes across genotypes with elevated or depleted DA levels which was reverted to wild type levels in specific rescue lines. Taken together, our results reveal a novel sexually dimorphic involvement of DA in senescence characteristics of D. melanogaster.Item dtorsin, the Drosophila Ortholog of the Early-Onset Dystonia TOR1A (DYT1), Plays a Novel Role in Dopamine Metabolism(PLOS, 2011) Wakabayashi-Ito, Noriko; Doherty, Olugbenga M.; Moriyama, Hideaki; Breakefield, Xandra O.; Gusella, James F.; O'Donnell, Janis M.; Ito, Naoto; Harvard University; Massachusetts General Hospital; University of Alabama Tuscaloosa; University of Nebraska Lincoln; Harvard Medical SchoolDystonia represents the third most common movement disorder in humans. At least 15 genetic loci (DYT1-15) have been identified and some of these genes have been cloned. TOR1A (formally DYT1), the gene responsible for the most common primary hereditary dystonia, encodes torsinA, an AAA ATPase family protein. However, the function of torsinA has yet to be fully understood. Here, we have generated and characterized a complete loss-of-function mutant for dtorsin, the only Drosophila ortholog of TOR1A. Null mutation of the X-linked dtorsin was semi-lethal with most male flies dying by the pre-pupal stage and the few surviving adults being sterile and slow moving, with reduced cuticle pigmentation and thin, short bristles. Third instar male larvae exhibited locomotion defects that were rescued by feeding dopamine. Moreover, biochemical analysis revealed that the brains of third instar larvae and adults heterozygous for the loss-of-function dtorsin mutation had significantly reduced dopamine levels. The dtorsin mutant showed a very strong genetic interaction with Pu (Punch: GTP cyclohydrolase), the ortholog of the human gene underlying DYT14 dystonia. Biochemical analyses revealed a severe reduction of GTP cyclohydrolase protein and activity, suggesting that dtorsin plays a novel role in dopamine metabolism as a positive-regulator of GTP cyclohydrolase protein. This dtorsin mutant line will be valuable for understanding this relationship and potentially other novel torsin functions that could play a role in human dystonia.Item Effects of transition metal cationization on peptide dissociation by mass spectrometry(University of Alabama Libraries, 2011) Watson, Heather Malone; Cassady, Carolyn J.; University of Alabama TuscaloosaPeptide sequencing is fundamental to understanding a protein's structure and function. The field of proteomics is dedicated to how these aspects relate to human health and disease. Unfortunately, the majority of peptides and proteins are not fully sequenced. In mass spectrometry, this is often due to spectral complications and incomplete fragmentation. There is a need to develop new sample preparation techniques or dissociation methods to increase sequence information. The dissociation of transition metal-cationized peptides by collision-induced dissociation (CID), electron-transfer dissociation (ETD), and electron-transfer collisionally activated dissociation (ETcaD) has been investigated in a quadrupole ion trap (QIT). The resulting mass spectra provide a wealth of information about the primary structures of the peptides. Using transition metal ions as cationizing reagents proves beneficial to peptide sequencing by CID and, in some cases, is better than the analysis of protonated species. For instance, spectra obtained from CID of singly and doubly charged Cu(II)-heptaalanine ions, [M + Cu - H]^+ and [M + Cu]^2, are complementary and together provide cleavage at every residue and no neutral losses. This contrasts with protonated heptaalanine, [M + H]^+, which results in fewer backbone cleavages by CID and does not allow sequencing of the first three residues. Multiply charged precursor ions are required in order to carry out ETD and ETcaD. This can be problematic for acidic or neutral peptides. This work demonstrates that addition of transition metals as a cationizing reagent allows peptides to be submitted to ETD and ETcaD that do not otherwise form multiply charged precursors. ETD spectra were less complex than those produced by CID. ETcaD increases backbone cleavages for all samples studied relative to ETD. In addition, complexes that result in very few cleavages by CID are cleaved at every residue when submitted to ETcaD. Evidence for macrocyclic metallated a- and b-ions is found in ETD and ETcaD spectra in the form of nonsequential product ions. The sequence (pEEEEGDD) of the peptide component of biologically derived low-molecular-weight chromium binding substance (LMWCr) is obtained as a result of extensive mass spectrometric studies. LMWCr is proposed to be involved in carbohydrate metabolism. The sequencing of the peptide component of LMWCr by MS represents a potentially significant milestone towards understanding the pharmacological role of chromium at a molecular level.Item The Glycolytic Enzyme, GPI, Is a Functionally Conserved Modifier of Dopaminergic Neurodegeneration in Parkinson's Models(Cell Press, 2014) Knight, Adam L.; Yan, Xiaohui; Hamamichi, Shusei; Ajjuri, Rami R.; Mazzulli, Joseph R.; Zhang, Mike W.; Daigle, J. Gavin; Zhang, Siyuan; Borom, Akeem R.; Roberts, Lindsay R.; Lee, S. Kyle; DeLeon, Susan M.; Viollet-Djelassi, Coralie; Krainc, Dimitri; O'Donnell, Janis M.; Caldwell, Kim A.; Caldwell, Guy A.; University of Alabama Tuscaloosa; University of Alabama Birmingham; Harvard University; Massachusetts General Hospital; University of Oxford; Wellcome Centre for Human Genetics; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC); Babraham InstituteNeurodegenerative diseases represent an increasing burden in our aging society, yet the underlying metabolic factors influencing onset and progression remain poorly defined. The relationship between impaired IGF-1/insulin-like signaling (IIS) and life-span extension represents an opportunity to investigate the interface of metabolism with age-associated neurodegeneration. Using data sets of established DAF-2/IIS-signaling components in Caenorhabditis elegans, we conducted systematic RNAi screens in worms to select for daf-2-associated genetic modifiers of alpha-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson's disease. An outcome of this strategy was the identification of GPI-1/GPI, an enzyme in glucose metabolism, as a daf-2-regulated modifier that acts independent of the downstream cytoprotective transcription factor DAF-16/FOXO to modulate neuroprotection. Subsequent mechanistic analyses using Drosophila and mouse primary neuron cultures further validated the conserved nature of GPI neuroprotection from alpha-synuclein proteotoxicity. Collectively, these results support glucose metabolism as a conserved functional node at the intersection of proteostasis and neurodegeneration.Item Hydrogen deuterium exchange mass spectrometry for protein-protein interaction and structural dynamics(University of Alabama Libraries, 2013) Singh, Harsimran; Busenlehner, Laura S.; University of Alabama TuscaloosaHydrogen deuterium exchange mass spectrometry has emerged as an important technique to probe protein structure and conformational dynamics. The rate of exchange of hydrogen with deuterium by the peptide backbone is dependent on the solvent accessibility, extent of hydrogen bonding in secondary structural elements and protein dynamics. The extent and the rate of deuterium incorporation are affected by changes in protein structure, interaction with ligand, protein-protein interaction and environmental factors such as pH and temperature. These conformational changes can be global and/or local. The increase in the mass is used to localize the deuterium incorporation after pepsin digestion of the protein and analysis by electrospray ionization mass spectrometry. In this dissertation traditional HDX-MS and a new deuterium trapping assay were used to probe the interaction sites between E. coli cysteine desulfurase SufS and acceptor protein SufE. SufS and SufE form an important part of the SUF pathway, essential for the biosynthesis of Fe-S clusters under oxidative stress and iron depletion conditions. In addition, SufE is known to stimulate SufS cysteine desulfurase activity, but the mechanism is unknown. The HDX-MS results show that the regions affected by the SufS-SufE interaction are dependent on the catalytic intermediate states of the two proteins. HDX-MS was also used to probe the conformational changes resulting upon persulfuration of SufS of Cys364 in the active site. The persulfuration of SufS not only affected regions in the active site cavity, but also had other conformational changes in more distal regions. Based on our findings a model for the interaction SufS and SufE was proposed. A mechanism for the enhancement of SufS cysteine desulfurase activity upon interaction with SufE was also postulated. In all this work demonstrates that hydrogen deuterium exchange mass spectrometry and the deuterium trapping methodology optimized for this system can be easily and effectively used to study the protein-protein interactions and the accompanying changes in structural dynamics for other proteins. Deuterium trapping was demonstrated to be fast, sensitive and reliable method to deduce the changes in solvent accessibility between two or more states of a protein. Both techniques can easily be applied to large number of protein complexes to determine the regions of interaction as well as gain mechanistic information not available through traditional methods such as X-ray crystallography and NMR.Item Innate immune responses to paraquat exposure in a Drosophila model of Parkinson's disease(Nature Portfolio, 2019) Maitra, Urmila; Scaglione, Michael N.; Chtarbanova, Stanislava; O'Donnell, Janis M.; University of Alabama TuscaloosaParkinson's disease (PD) is a progressive, neurodegenerative movement disorder characterized by the loss of dopaminergic (DA) neurons. Limited understanding of the early molecular pathways associated with the demise of DA neurons, including those of inflammatory exacerbation of neurodegeneration, is a major impediment to therapeutic development. Recent studies have implicated gene-environment interactions in PD susceptibility. We used transcriptomic profiling in a Drosophila PD model in response to paraquat (PQ)-induced oxidative stress to identify pre-symptomatic signatures of impending neuron dysfunction. Our RNAseq data analysis revealed extensive regulation of innate immune response genes following PQ ingestion. We found that PQ exposure leads to the activation of the NF-kappa B transcription factor, Relish, and the stress signaling factor JNK, encoded by the gene basket in Drosophila. Relish knockdown in the dopaminergic neurons confers PQ resistance and rescues mobility defects and DA neuron loss. Furthermore, PQ-induced toxicity is mediated through the immune deficiency signaling pathway. Surprisingly, the expression of Relish-dependent anti-microbial peptide (AMPS) genes is suppressed upon PQ exposure causing increased sensitivity to Gram-negative bacterial infection. This work provides a novel link between PQ exposure and innate immune system modulation underlying environmental toxin-induced neurodegeneration, thereby underscoring the role of the innate immune system in PD pathogenesis.Item Investigation of regulatory and functional diversity in an enzyme superfamily(University of Alabama Libraries, 2015) Kumar, Garima; Frantom, Patrick A.; University of Alabama TuscaloosaUnderstanding the evolution of functional and regulatory diversity in enzyme superfamilies addresses a fundamental biochemical problem by improving our ability to identify and exploit structure/function relationships. It opens up the possibility of engineering naturally occurring enzymes and designing new scaffolds for user defined goals. In an attempt to achieve this goal the DRE-TIM metallolyase superfamily has been investigated using bioinformatic and biochemical tools. Analysis of one of the member subgroups, the Claisen condensation-like (CC-like) subgroup, identified the presence of an interesting pattern of functional and regulatory diversity. The CC-like subgroup has ~4300 sequences that catalyze the condensation of acetyl-CoA with six different -keto acids. While some sequentially similar members of this subgroup exhibit distinct substrate specificities, some members with low sequence identities display identical activities. Though the underlying causes of these phenomena are still unknown, evolution of either regulatory and/or functional mechanisms could have generated these discrepancies. To explore diversity in the regulatory mechanisms, two evolutionarily distinct versions of -isopropylmalate synthase (IPMS) enzymes were analyzed. IPMS from Methanococcus jannaschii (MjIPMS) was investigated, and compared with the well characterized IPMS from Mycobacterium tuberculosis (MtIPMS). Isotope effects revealed the conservation of the mechanism of regulation in these different versions of IPMS enzymes. The presence of identical feedback regulation mechanisms in distinct enzymes indicates the complexity of identifying structure/function relationships in multidomain allosteric enzymes. To understand the functional diversity in the CC-like subgroup, IPMS and citramalate synthase (CMS) from Methanococcus jannaschii, MjIPMS and MjCMS, respectively were investigated. MjIPMS and MjCMS share ~50% sequence identity and exhibit distinct substrate specificities for -keto acids. While rational design of substitutions to modulate the active site architecture provided some insight into the mechanism of substrate selectivity for MjIPMS, the mechanism of substrate selection is still unknown for MjCMS. The MjCMS active site was further explored by employing directed evolution tools involving irrational design of substitutions and genetic selection for IPMS activity. Irrational substitutions have been able to deliver initial candidates of MjCMS variants with slightly altered substrate selectivity. Characterization of these libraries should provide significant insight into the mechanism of functional diversity in the DRE-TIM metallolyase superfamily.Item Low-molecular-weight chromium-binding substance: advanced studies from aves to human(University of Alabama Libraries, 2009) Chen, Yuan; Vincent, John B.; University of Alabama TuscaloosaChromium has been observed to play a role in maintaining proper carbohydrate and lipid metabolism of mammals. One of the potentially biological active forms of chromium in vitro is low-molecular-weight chromium-binding substance (LMWCr), which has been proposed to amplify the insulin cascade by binding with insulin receptor. LWMCr is a small bio-molecule (<1500 Da) containing a carboxylate-rich polypeptide with four bound chromic ions. LMWCr's (according to its amino acid composition and mass spectrum) were successfully isolated from chicken and alligator livers, as well as from human urine, using a modified method. The extreme hydrophilicity of the peptide and the tightly bound Cr(III) are two major hurdles to produce a stable end-product for mass spectrometry (MS) or high-performance liquid chromatography (HPLC) analysis. Treating bovine LMWCr with trifluoroacetic acid and application to a graphite powder micro-column was used to generate a heptapeptide fragment, and the peptide sequence was analyzed by mass spectrometry (MS) and tandem MS (MS/MS). Two candidate sequences, EEEEGDD and EEEGEDD, were identified; the mass spectrum of the former sequence is more similar to that of the LMWCr fragment. Langmuir isotherm and Hill plots were used to analyze the binding constants of chromic ions to synthetic peptides similar in composition to LMWCr and apoLMWCr. The sequence pEEEEGDD can bind 4 chromic ions per peptide as apoLMWCr does, while the other sequences examined only bind two chromic ions. Studies to further elucidate the structure of LMWCr are ongoing.Item Modulation of social space by dopamine in Drosophila melanogaster, but no effect on the avoidance of the Drosophila stress odorant(Royal Society of London, 2017) Fernandez, Robert W.; Akinleye, Adesanya A.; Nurilov, Marat; Feliciano, Omar; Lollar, Matthew; Aijuri, Rami R.; O'Donnell, Janis M.; Simon, Anne F.; Yale University; York College NY (CUNY); University of Alabama Tuscaloosa; Western University (University of Western Ontario)Appropriate response to others is necessary for social interactions. Yet little is known about how neurotransmitters regulate attractive and repulsive social cues. Using genetic and pharmacological manipulations in Drosophila melanogaster, we show that dopamine is contributing the response to others in a social group, specifically, social spacing, but not the avoidance of odours released by stressed flies (dSO). Interestingly, this dopamine-mediated behaviour is prominent only in the day-time, and its effect varies depending on tissue, sex and type of manipulation. Furthermore, alteration of dopamine levels has no effect on dSO avoidance regardless of sex, which suggests that a different neurotransmitter regulates this response.Item Mutant human torsinA, responsible for early-onset dystonia, dominantly suppresses GTPCH expression, dopamine levels and locomotion in Drosophila melanogaster(Company of Biologists, 2015) Wakabayashi-Ito, Noriko; Ajjuri, Rami R.; Henderson, Benjamin W.; Doherty, Olugbenga M.; Breakefield, Xandra O.; O'Donnell, Janis M.; Ito, Naoto; Harvard University; Massachusetts General Hospital; Harvard Medical School; University of Alabama TuscaloosaDystonia represents the third most common movement disorder in humans with over 20 genetic loci identified. TOR1A (DYT1), the gene responsible for the most common primary hereditary dystonia, encodes torsinA, an AAA ATPase family protein. Most cases of DYT1 dystonia are caused by a 3 bp (Delta GAG) deletion that results in the loss of a glutamic acid residue (Delta E302/303) in the carboxyl terminal region of torsinA. This torsinA Delta E mutant protein has been speculated to act in a dominant-negative manner to decrease activity of wild type torsinA. Drosophila melanogaster has a single torsin-related gene, dtorsin. Null mutants of dtorsin exhibited locomotion defects in third instar larvae. Levels of dopamine and GTP cyclohydrolase (GTPCH) proteins were severely reduced in dtorsin-null brains. Further, the locomotion defect was rescued by the expression of human torsinA or feeding with dopamine. Here, we demonstrate that human torsinA Delta E dominantly inhibited locomotion in larvae and adults when expressed in neurons using a pan-neuronal promoter Elav. Dopamine and tetrahydrobiopterin (BH4) levels were significantly reduced in larval brains and the expression level of GTPCH protein was severely impaired in adult and larval brains. When human torsinA and torsinA Delta E were co-expressed in neurons in dtorsin-null larvae and adults, the locomotion rates and the expression levels of GTPCH protein were severely reduced. These results support the hypothesis that torsinA Delta E inhibits wild type torsinA activity. Similarly, neuronal expression of a Drosophila Dtorsin Delta E equivalent mutation dominantly inhibited larval locomotion and GTPCH protein expression. These results indicate that both torsinA Delta E and DtorsinDE act in a dominant-negative manner. We also demonstrate that Dtorsin regulates GTPCH expression at the post-transcriptional level. This Drosophila model of DYT1 dystonia provides an important tool for studying the differences in the molecular function between the wild type and the mutant torsin proteins.Item Novel Whole-tissue Quantitative Assay of Nitric Oxide Levels in Drosophila Neuroinflammatory Response(MyJove Corporation, 2013) Ajjuri, Rami R.; O'Donnell, Janis M.; University of Alabama TuscaloosaNeuroinflammation is a complex innate immune response vital to the healthy function of the central nervous system (CNS). Under normal conditions, an intricate network of inducers, detectors, and activators rapidly responds to neuron damage, infection or other immune infractions. This inflammation of immune cells is intimately associated with the pathology of neurodegenerative disorders, such as Parkinson's disease (PD), Alzheimer's disease and ALS. Under compromised disease states, chronic inflammation, intended to minimize neuron damage, may lead to an over-excitation of the immune cells, ultimately resulting in the exacerbation of disease progression. For example, loss of dopaminergic neurons in the midbrain, a hallmark of PD, is accelerated by the excessive activation of the inflammatory response. Though the cause of PD is largely unknown, exposure to environmental toxins has been implicated in the onset of sporadic cases. The herbicide paraquat, for example, has been shown to induce Parkinsonian-like pathology in several animal models, including Drosophila melanogaster. Here, we have used the conserved innate immune response in Drosophila to develop an assay capable of detecting varying levels of nitric oxide, a cell-signaling molecule critical to the activation of the inflammatory response cascade and targeted neuron death. Using paraquat-induced neuronal damage, we assess the impact of these immune insults on neuroinflammatory stimulation through the use of a novel, quantitative assay. Whole brains are fully extracted from flies either exposed to neurotoxins or of genotypes that elevate susceptibility to neurodegeneration then incubated in cell-culture media. Then, using the principles of the Griess reagent reaction, we are able to detect minor changes in the secretion of nitric oxide into cell-culture media, essentially creating a primary live-tissue model in a simple procedure. The utility of this model is amplified by the robust genetic and molecular complexity of Drosophila melanogaster, and this assay can be modified to be applicable to other Drosophila tissues or even other small, whole-organism inflammation models.Item Perturbations in dopamine synthesis lead to discrete physiological effects and impact oxidative stress response in Drosophila(Pergamon, 2015) Hanna, Marley E.; Bednarova, Andrea; Rakshit, Kuntol; Chaudhuri, Anathbandhu; O'Donnell, Janis M.; Krishnan, Natraj; Mississippi State University; Czech Academy of Sciences; Biology Centre of the Czech Academy of Sciences; University of South Bohemia Ceske Budejovice; Mayo Clinic; Stillman College; University of Alabama TuscaloosaThe impact of mutations in four essential genes involved in dopamine (DA) synthesis and transport on longevity, motor behavior, and resistance to oxidative stress was monitored in Drosophila melanogaster. The fly lines used for this study were: (i) a loss of function mutation in Catecholamines up (Catsup(26)), which is a negative regulator of the rate limiting enzyme for DA synthesis, (ii) a mutant for the gene pale (ple(2)) that encodes for the rate limiting enzyme tyrosine hydroxylase (TH), (iii) a mutant for the gene Punch (Pu-Z22) that encodes guanosine triphosphate cyclohydrolase, required for TH activity, and (iv) a mutant in the vesicular monoamine transporter (VMAT(Delta 14)), which is required for packaging of DA as vesicles inside DA neurons. Median lifespans of ple(2), Pu-Z22 and VMAT(Delta 14) mutants were significantly decreased compared to Catsup(26) and wild type controls that did not significantly differ between each other. Catsup(26) flies survived longer when exposed to hydrogen peroxide (80 mu M) or paraquat (10 mM) compared to ple2, Pu-Z22 or VMAT(Delta 14) and controls. These flies also exhibited significantly higher negative geotaxis activity compared to pie?, Pu-Z22, VMAT(Delta 14) and controls. All mutant flies demonstrated rhythmic circadian locomotor activity in general, albeit Catsup(26) and VMAT(Delta 14) flies had slightly weaker rhythms. Expression analysis of some key antioxidant genes revealed that glutathione S-transferase Omega-1 (GSTO1) expression was significantly up-regulated in all DA synthesis pathway mutants and especially in Catsup(26) and VMAT(Delta 14) flies at both mRNA and protein levels. Taken together, we hypothesize that DA could directly influence GSTO1 transcription and thus play a significant role in the regulation of response to oxidative stress. Additionally, perturbations in DA synthesis do not appear to have a significant impact on circadian locomotor activity rhythms per se, but do have an influence on general locomotor activity levels. (C) 2015 Elsevier Ltd. All rights reserved.