functional-analysis-of-the-larval-feeding-circuit-in-drosophila

Functional Analysis of the Larval Feeding Circuit in <i>Drosophila</i>

The serotonergic  feeding circuit in Drosophila  melanogaster larvae can be used to investigate neuronal substrates of  critical importance during the ...

Saint Louis University School of Medicine

We have identified several GABAergic-modulated behaviors in Drosophila melanogaster by employing a pharmacological approach to disrupt GABA transporter function in vivo. Systemic treatment of adult female flies with the GABA transport inhibitors DL-2,4-diaminobutyric acid (DABA) or R,S-nipecotic acid (NipA), resulted in diminished locomotor activity, deficits in geotaxis, and the induction of convulsive behaviors with a secondary loss of the righting reflex. Pharmacological evidence suggested that the observed behavioral phenotypes were specific to disruption of GABA transporter function and GABAergic activity. The effects of GABA reuptake inhibitors on locomotor activity were dose dependent, pharmacologically distinct, and paralleled their known effects in mammalian systems. Recovery of normal locomotor activity and the righting reflex in DABA- and NipA-treated flies was achieved by coadministration of bicuculline (BIC), a GABA receptor antagonist that supresses GABAergic activity in mammals. Recovery of these behaviors was also achieved by coadministration of gabapentin, an anticonvulsant agent that interacts with mammalian GABAergic systems. Finally, behavioral effects were selective because other specific behaviors such as feeding activity and female sexual receptivity were not affected. Related pharmacological analyses performed in vitro on isolated Drosophila synaptic plasma membrane vesicles demonstrated high affinity, saturable uptake mechanisms for [3H]-GABA; further competitive inhibition studies with DABA and NipA demonstrated their ability to inhibit [3H]-GABA transport. The existence of experimentally accessible GABA transporters in Drosophila that share conserved pharmacological properties with their mammalian counterparts has resulted in the identification of specific behaviors that are modulated by GABA.

Pharmacological evidence for GABAergic regulation of specific behaviors in Drosophila melanogaster.

Vascular endothelial growth factors (VEGFs) stimulate endothelial cell growth through interactions with their tyrosine kinase receptors to stimulate intracellular signaling events. This culminates in the expression of specific gene products that induce a cellular response in numerous physiological processes, including hematopoeisis, oncogenesis and embryogenesis. The primordial function of VEGF can be revealed by studying VEGF-mediated signaling pathways in the powerful and tractable model system, Drosophila melanogaster, which has proved invaluable in furthering our understanding of conserved developmental themes.

Talking the talk: the role of VEGF proteins in cell signaling.

We have identified specific GABAergic-modulated behaviors in the juvenile stage of the fruit fly, Drosophila melanogaster via systemic treatment of second instar larvae with the potent GABA transport inhibitor DL-2,4-diaminobutyric acid (DABA). DABA significantly inhibited motor-controlled body wall and mouth hook contractions and impaired rollover activity and contractile responses to touch stimulation. The perturbations in locomotion and rollover activity were reminiscent of corresponding DABA-induced deficits in locomotion and the righting reflex observed in adult flies. The effects were specific to these motor-controlled behaviors, because DABA-treated larvae responded normally in olfaction and phototaxis assays. Recovery of these behaviors was achieved by cotreatment with the vertebrate GABA(A) receptor antagonist picrotoxin. Pharmacological studies performed in vitro with plasma membrane vesicles isolated from second instar larval tissues verified the presence of high-affinity, saturable GABA uptake mechanisms. GABA uptake was also detected in plasma membrane vesicles isolated from behaviorally quiescent stages. Competitive inhibition studies of [3H]-GABA uptake into plasma membrane vesicles from larval and pupal tissues with either unlabeled GABA or the transport inhibitors DABA, nipecotic acid, or valproic acid, revealed differences in affinities. GABAergic-modulation of motor behaviors is thus conserved between the larval and adult stages of Drosophila, as well as in mammals and other vertebrate species. The pharmacological studies reveal shared conservation of GABA transport mechanisms between Drosophila and mammals, and implicate the involvement of GABA and GABA transporters in regulating physiological processes distinct from neurotransmission during behaviorally quiescent stages of development.

GABAergic modulation of motor-driven behaviors in juvenile Drosophila and evidence for a nonbehavioral role for GABA transport.

In Drosophila melanogaster, serotonin (5-hydroxytryptamine, 5-HT) is required for both very early non-neuronal developmental events, and in the CNS as a neurotransmitter to modulate behavior. 5-HT is synthesized, at least in part, by the actions of Drosophila tryptophan-phenylalanine hydroxylase (DTPH), a dual function enzyme that hydroxylates both phenylalanine and tryptophan. DTPH is expressed in numerous tissues as well as dopaminergic and serotonergic neurons, but it does not necessarily function as both enzymes in these tissues. Deficiencies in DTPH could affect the production of dopamine and serotonin, and thus dopaminergic and serotonergic signaling pathways. In this paper, we show that DTPH exhibits differential hydroxylase activity based solely on substrate. When DTPH uses phenylalanine as a substrate, regulatory control (end product inhibition, decreased PAH activity following phosphorylation, catecholamine inhibition) is observed that is not seen when the enzyme uses tryptophan as a substrate. These studies suggest that regulation of DTPH enzymatic activity occurs, at least in part, through the actions of its substrate.

Substrate regulation of serotonin and dopamine synthesis in Drosophila.

Annotation of the sequenced Drosophila genome suggested the presence of an additional enzyme with extensive homology to mammalian tryptophan hydroxylase, which we have termed DTRH. In this work, we show that enzymatic analyses of the putative DTRH enzyme expressed in Escherichia coli confirm that it acts as a tryptophan hydroxylase but can also hydroxylate phenylalanine, in vitro. Building upon the knowledge gained from the work in mice and zebrafish, it is possible to hypothesize that DTRH may be primarily neuronal in function and expression, and DTPH, which has been previously shown to have phenylalanine hydroxylation as its primary role, may be the peripheral tryptophan hydroxylase in Drosophila. The experiments presented in this report also show that DTRH is similar to DTPH in that it exhibits differential hydroxylase activity based on substrate. When DTRH uses tryptophan as a substrate, substrate inhibition, catecholamine inhibition, and decreased tryptophan hydroxylase activity in the presence of serotonin synthesis inhibitors are observed. When DTRH uses phenylalanine as a substrate, end product inhibition, increased phenylalanine hydroxylase activity after phosphorylation by cAMP-dependent protein kinase, and a decrease in phenylalanine hydroxylase activity in the presence of the serotonin synthesis inhibitor, alpha-methyl-(DL)-tryptophan are observed. These experiments suggest that the presence of distinct tryptophan hydroxylase enzymes may be evolutionarily conserved and serve as an ancient mechanism to appropriately regulate the production of serotonin in its target tissues.

Serotonin synthesis by two distinct enzymes in Drosophila melanogaster.

Behaviors modulated by dopamine appear to be conserved across species. In the model system Drosophila melanogaster, as in mammals, dopamine modulates female sexual receptivity, a simple form of learning and responses to drugs of abuse. Synthesis, reuptake and binding of dopamine are also evolutionarily conserved. Since stress has been shown to affect dopaminergic signaling pathways in mammals, we investigated the consequences of exposure to diverse stressors on dopaminergic physiology in the fruit fly, D. melanogaster. Animals were exposed to a metabolic stress (starvation), an oxidative stress (via the superoxide anion generator paraquat) or a mechanical stress (gentle vortexing). Sexual maturity, reproductive status, gender and type of stress differentially affected survival. The stress paradigms also resulted in alterations in the activity of tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis. Exposure to these stressors perturbed female sexual receptivity and ovarian development, which are modulated by dopamine, suggesting that dopaminergic physiology is affected as a consequence of stress. Transgenic Drosophila with reduced levels of neuronal dopamine displayed an altered response to these stressors, suggesting that, as in mammals, dopamine is a key element in the stress response.

Stress affects dopaminergic signaling pathways in Drosophila melanogaster.

Dopamine modulates several behavioral and developmental events; in the fruit fly Drosophila melanogaster, dopamine is a neurotransmitter, a neuromodulator, and a developmental signal. Studies in mammals suggest that these diverse roles for dopamine have been evolutionarily conserved. Fundamental regulation of dopamine occurs via tyrosine hydroxylase (TH), the first and rate-limiting enzyme in the catecholamine biosynthetic pathway. Mammalian TH is acutely regulated via phosphorylation-dephosphorylation mechanisms, which occur as a direct consequence of nerve stimulation. We have shown that the Drosophila homolog of TH, DTH, shares over 50% sequence identity with mammalian TH, and the serine residue corresponding to the major site of phosphorylation is conserved. We demonstrate using recombinant DTH protein generated in E. coli that its regulatory biochemical mechanisms closely parallel those from mammals. Drosophila thus provides a highly conserved and tractable model system in which to test the functional consequences of perturbing TH activity by acute regulatory mechanisms.

Biochemical conservation of recombinant Drosophila tyrosine hydroxylase with its mammalian cognates.

&#x5E15;&#x91D1;&#x68EE;&#x75C5; (PD) &#x662F;&#x6700;&#x5E38;&#x89C1;&#x7684;&#x795E;&#x7ECF;&#x9000;&#x884C;&#x6027;&#x8FD0;&#x52A8;&#x969C;&#x788D;&#x3002;PINK1 &#x57FA;&#x56E0;&#x7684;&#x7A81;&#x53D8;&#x76F8;&#x8FDE;&#x7684;&#x5E38;&#x67D3;&#x8272;&#x4F53;&#x663E;&#x6027;&#x9690;&#x6027;&#x65E9;&#x671F;&#x53D1;&#x75C5;&#x5BB6;&#x65CF;&#x5F62;&#x6001; PD&#x3002;PINK1 &#x7684;&#x751F;&#x7406;&#x529F;&#x80FD;&#x548C;&#x75C5;&#x7406;&#x5F02;&#x5E38;&#x7684; PD &#x5173;&#x8054; PINK1 &#x7A81;&#x53D8;&#x662F;&#x4E3B;&#x8981;&#x662F;&#x672A;&#x77E5;&#x7684;&#x3002;&#x6211;&#x4EEC;&#x5728;&#x8FD9;&#x91CC;&#x5C55;&#x793A;&#x7684;&#x706D;&#x6D3B;&#x7684;&#x679C;&#x8747; PINK1 (dPINK1) &#x4E2D;&#x7684;&#x591A;&#x5DF4;&#x80FA;&#x80FD;&#x795E;&#x7ECF;&#x5143;&#x7684;&#x9010;&#x6B65;&#x4E27;&#x5931;&#x548C; ommatidial &#x53D8;&#x6027;&#x7684;&#x590D;&#x773C;&#x4F7F;&#x7528; RNAi &#x7ED3;&#x679C;&#xFF0C;&#x5176;&#x4E2D;&#x6551;&#x8D77;&#x8868;&#x8FBE;&#x7684;&#x4EBA;&#x7C7B; PINK1 (hPINK1)&#x3002;&#x4EBA;&#x7C7B; SOD1 &#x7684;&#x8868;&#x8FBE;&#x6291;&#x5236;&#x795E;&#x7ECF;&#x53D8;&#x6027;&#x81F4; dPINK1 &#x706D;&#x6D3B;&#x3002;&#x6B64;&#x5916;&#xFF0C;&#x6CBB;&#x7597; dPINK1 RNAi &#x82CD;&#x8747;&#x8D85;&#x6C27;&#x5316;&#x7269;&#x6B67;&#x5316;&#x9176;&#x548C;&#x7EF4;&#x751F;&#x7D20; E &#x7684;&#x6297;&#x6C27;&#x5316;&#x5242;&#x6709;&#x663E;&#x8457;&#x7684;&#x6291;&#x5236; ommatidial &#x53D8;&#x6027;&#x3002;&#x56E0;&#x6B64;&#xFF0C;dPINK1 &#x53D1;&#x6325;&#x53D1;&#x6325;&#x91CD;&#x8981;&#x4F5C;&#x7528;&#xFF0C;&#x901A;&#x8FC7;&#x9632;&#x6B62;&#x795E;&#x7ECF;&#x5143;&#x4ECE;&#x6B63;&#x5728;&#x8FDB;&#x884C;&#x7684;&#x6C27;&#x5316;&#x5E94;&#x6FC0;&#xFF0C;&#x4ECE;&#x800C;&#x8868;&#x660E;&#x5176;&#x4E2D; PINK1 &#x51FD;&#x6570;&#x4E2D;&#x7684;&#x51CF;&#x5C11;&#x4F1A;&#x5BFC;&#x81F4; PD &#x76F8;&#x5173;&#x795E;&#x7ECF;&#x53D8;&#x6027;&#x7684;&#x6F5C;&#x5728;&#x673A;&#x5236;&#x7EF4;&#x6301;&#x795E;&#x7ECF;&#x7EC6;&#x80DE;&#x7684;&#x751F;&#x5B58;&#x3002;

&#x6297;&#x6C27;&#x5316;&#x5242;&#x4FDD;&#x62A4;&#x679C;&#x8747; PINK1 &#x4F9D;&#x8D56;&#x7684;&#x591A;&#x5DF4;&#x80FA;&#x80FD;&#x795E;&#x7ECF;&#x5143;&#x3002;

Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder. Mutations in the PINK1 gene are linked to the autosomal recessive early onset familial form of PD. The physiological function of PINK1 and pathological abnormality of PD-associated PINK1 mutants are largely unknown. We here show that inactivation of Drosophila PINK1 (dPINK1) using RNAi results in progressive loss of dopaminergic neurons and in ommatidial degeneration of the compound eye, which is rescued by expression of human PINK1 (hPINK1). Expression of human SOD1 suppresses neurodegeneration induced by dPINK1 inactivation. Moreover, treatment of dPINK1 RNAi flies with the antioxidants SOD and vitamin E significantly inhibits ommatidial degeneration. Thus, dPINK1 plays an essential role in maintaining neuronal survival by preventing neurons from undergoing oxidative stress, thereby suggesting a potential mechanism by which a reduction in PINK1 function leads to PD-associated neurodegeneration.

Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila.

La maladie de Parkinson (PD) est le trouble du mouvement le plus fr&#xE9;quent neurod&#xE9;g&#xE9;n&#xE9;rative. Des mutations dans le g&#xE8;ne PINK1 sont li&#xE9;s &#xE0; la forme autosomique r&#xE9;cessive apparition pr&#xE9;coce familiale de maladie de Parkinson. La fonction physiologique de PINK1 et pathologique anomalie de mutants PINK1 PD-associ&#xE9;s sont largement inconnues. Nous ici montrent que l&#x26;#39;inactivation de la drosophile PINK1 (dPINK1) en utilisant les r&#xE9;sultats ARNi dans la perte progressive des neurones dopaminergiques et dans la d&#xE9;g&#xE9;n&#xE9;rescence ommatidial de l&#x26;#39;&#x153;il compos&#xE9;, qui est sauv&#xE9; par l&#x26;#39;expression de PINK1 humaine (hPINK1). Expression de la SOD1 humaine supprime la neurod&#xE9;g&#xE9;n&#xE9;rescence induite par dPINK1 inactivation. En outre, le traitement des dPINK1 ARNi vole avec la SOD antioxydants et de vitamine E inhibe de mani&#xE8;re significative la d&#xE9;g&#xE9;n&#xE9;rescence ommatidial. Ainsi, dPINK1 joue un r&#xF4;le essentiel dans le maintien de la survie neuronale en emp&#xEA;chant les neurones de subir le stress oxydatif, ce qui sugg&#xE8;re un m&#xE9;canisme potentiel par lequel une r&#xE9;duction de la fonction PINK1 conduit &#xE0; PD neurod&#xE9;g&#xE9;n&#xE9;rescence associ&#xE9;e &#xE0; la.

Les antioxydants prot&#xE8;gent PINK1-d&#xE9;pendants neurones dopaminergiques dans la drosophile

Morbus Parkinson (PD) ist die h&auml;ufigste Neurodegenerative Bewegungsst&ouml;rung. Die autosomal rezessive fr&uuml;h beginnende famili&auml;re Form der PD sind Mutationen im Gen PINK1 verbunden. Die physiologische Funktion von PINK1 und pathologische Ver&auml;nderungen von PD-assoziierte PINK1 Mutanten sind weitgehend unbekannt. Wir zeigen hier die Inaktivierung von Drosophila PINK1 (dPINK1) mit RNAi-Ergebnisse, in progressiven Verlust der dopaminergen Neuronen und ommatidial Degeneration der Verbindung-Auge, wird die durch Ausdruck der menschlichen PINK1 gerettet (hPINK1). Ausdruck der menschlichen SOD1 unterdr&uuml;ckt Neurodegeneration induziert durch dPINK1 Inaktivierung. Dar&uuml;ber hinaus hemmt die Behandlung von dPINK1, die RNAi deutlich mit den Antioxidantien SOD und Vitamin E fliegt ommatidial Entartung. DPINK1 spielt daher eine wesentliche Rolle bei der Aufrechterhaltung der neuronalen &Uuml;berleben von Neuronen in oxidativen Stress, dadurch schl&auml;gt einen m&ouml;glichen Mechanismus durch den R&uuml;ckgang PINK1-Funktion zu PD-assoziierte Neurodegeneration f&uuml;hrt zu verhindern.

Antioxidantien sch&uuml;tzen PINK1-abh&auml;ngige dopaminergen Neuronen in Drosophila.

Malattia di Parkinson (MdP) &egrave; il pi&ugrave; frequente disturbo del movimento neurodegenerative. Mutazioni nel gene PINK1 sono collegate alla forma autosomica recessiva precoce insorgenza familiare del PD. La funzione fisiologica di PINK1 e anormalit&agrave; patologica del PD-associated PINK1 mutanti sono in gran parte sconosciuto. Mostriamo qui tale inattivazione della drosofila PINK1 (dPINK1) mediante RNAi risultati nella progressiva perdita di Neuroni dopaminergici e ommatidial degenerazione dell&#39;occhio composto, che viene salvato da espressione di PINK1 umana (hPINK1). Espressione di SOD1 umana sopprime la neurodegenerazione indotta dall&#39;inattivazione di dPINK1. Inoltre, trattamento di dPINK1 che RNAi vola in modo significativo con gli antiossidanti SOD e la vitamina E inibisce la degenerazione ommatidial. Cos&igrave;, dPINK1 gioca un ruolo essenziale nel mantenimento della sopravvivenza neuronale impedendo i neuroni dallo stress ossidativo in corso, suggerendo cos&igrave; un potenziale meccanismo mediante il quale una riduzione nella funzione PINK1 porta alla neurodegenerazione associata a PD.

Antiossidanti proteggono i neuroni dopaminergici PINK1-dipendente in drosofila.

&#x30D1;&#x30FC;&#x30AD;&#x30F3;&#x30BD;&#x30F3;&#x75C5;&#xFF08;PD&#xFF09;&#x306F;&#x3001;&#x6700;&#x3082;&#x983B;&#x7E41;&#x306B;&#x795E;&#x7D4C;&#x904B;&#x52D5;&#x969C;&#x5BB3;&#x3067;&#x3059;&#x3002; PINK1&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x7A81;&#x7136;&#x5909;&#x7570;&#x306F;&#x3001;PD&#x306E;&#x5E38;&#x67D3;&#x8272;&#x4F53;&#x52A3;&#x6027;&#x907A;&#x4F1D;&#x306E;&#x65E9;&#x671F;&#x767A;&#x75C7;&#x578B;&#x5BB6;&#x65CF;&#x6027;&#x30D5;&#x30A9;&#x30FC;&#x30E0;&#x306B;&#x30EA;&#x30F3;&#x30AF;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002; PD&#x95A2;&#x9023;PINK1&#x306E;&#x5909;&#x7570;&#x4F53;&#x306E;PINK1&#x3068;&#x75C5;&#x7684;&#x7570;&#x5E38;&#x306E;&#x751F;&#x7406;&#x5B66;&#x7684;&#x6A5F;&#x80FD;&#x306F;&#x4E0D;&#x660E;&#x306A;&#x70B9;&#x304C;&#x591A;&#x3044;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x4F5C;&#x52D5;&#x6027;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x306E;&#x9032;&#x884C;&#x6027;&#x306E;&#x55AA;&#x5931;&#x3084;&#x4EBA;&#x9593;PINK1&#xFF08;hPINK1&#xFF09;&#x306E;&#x767A;&#x73FE;&#x306B;&#x3088;&#x3063;&#x3066;&#x6551;&#x51FA;&#x3055;&#x308C;&#x305F;&#x8907;&#x773C;&#x306E;&#x500B;&#x773C;&#x5909;&#x6027;&#x306B;&#x304A;&#x3051;&#x308B;RNAi&#x7D50;&#x679C;&#x3092;&#x7528;&#x3044;&#x3066;&#x30B7;&#x30E7;&#x30A6;&#x30B8;&#x30E7;&#x30A6;&#x30D0;&#x30A8;PINK1&#xFF08;dPINK1&#xFF09;&#x3068;&#x4E0D;&#x6D3B;&#x6027;&#x5316;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x30D2;&#x30C8;SOD1&#x306E;&#x767A;&#x73FE;&#x306F;dPINK1&#x4E0D;&#x6D3B;&#x5316;&#x306B;&#x3088;&#x308A;&#x8A98;&#x5C0E;&#x3055;&#x308C;&#x308B;&#x795E;&#x7D4C;&#x5909;&#x6027;&#x3092;&#x6291;&#x5236;&#x3057;&#x307E;&#x3059;&#x3002;&#x307E;&#x305F;&#x3001;dPINK1 RNAi&#x306E;&#x6CBB;&#x7642;&#x304C;&#x5927;&#x5E45;&#x306B;&#x500B;&#x773C;&#x306E;&#x5909;&#x6027;&#x3092;&#x6291;&#x5236;&#x3059;&#x308B;&#x6297;&#x9178;&#x5316;&#x7269;&#x8CEA;&#x306E;SOD&#x3068;&#x30D3;&#x30BF;&#x30DF;&#x30F3;E&#x3068;&#x98DB;&#x3076;&#x3002;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;dPINK1&#x305D;&#x308C;&#x306B;&#x3088;&#x3063;&#x3066;PINK1&#x6A5F;&#x80FD;&#x306E;&#x4F4E;&#x4E0B;&#x306F;&#x3001;PD-&#x95A2;&#x9023;&#x795E;&#x7D4C;&#x5909;&#x6027;&#x306B;&#x3064;&#x306A;&#x304C;&#x308B;&#x3053;&#x3068;&#x306B;&#x3088;&#x308A;&#x3001;&#x6F5C;&#x5728;&#x7684;&#x306A;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x3092;&#x793A;&#x5506;&#x3057;&#x3001;&#x9178;&#x5316;&#x30B9;&#x30C8;&#x30EC;&#x30B9;&#x3092;&#x53D7;&#x3051;&#x3066;&#x304B;&#x3089;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x3092;&#x9632;&#x6B62;&#x3059;&#x308B;&#x3053;&#x3068;&#x306B;&#x3088;&#x308A;&#x3001;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x306E;&#x751F;&#x5B58;&#x3092;&#x7DAD;&#x6301;&#x3059;&#x308B;&#x4E0A;&#x3067;&#x91CD;&#x8981;&#x306A;&#x5F79;&#x5272;&#x3092;&#x679C;&#x305F;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;

&#x6297;&#x9178;&#x5316;&#x4FDD;&#x8B77;&#x30B7;&#x30E7;&#x30A6;&#x30B8;&#x30E7;&#x30A6;&#x30D0;&#x30A8;&#x306E;PINK1&#x4F9D;&#x5B58;&#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x4F5C;&#x52D5;&#x6027;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;

&#xD30C; &#xD0A8; &#xC2A8; &#xBCD1; (PD) &#xAC00;&#xC7A5; &#xD754;&#xD55C; &#xC2E0;&#xACBD; &#xD1F4;&#xD589; &#xC131; &#xC6B4;&#xB3D9; &#xC7A5;&#xC560; &#xC774;&#xB2E4;. PINK1 &#xC720;&#xC804;&#xC790;&#xC758; &#xBCC0;&#xC774; &#xC0C1; &#xC5FC;&#xC0C9;&#xCCB4; &#xC5F4;&#xC131; &#xCD08;&#xAE30; &#xBC1C;&#xBCD1; &#xAC00;&#xC871; &#xD615;&#xD0DC;&#xC758; PD&#xC5D0; &#xC5F0;&#xACB0; &#xB429;&#xB2C8;&#xB2E4;. Pink1&#xC758; &#xC0DD;&#xB9AC; &#xC801; &#xAE30;&#xB2A5; &#xBC0F; &#xACBD;&#xCC30; &#xAD00;&#xB828; PINK1 &#xB3CC;&#xC5F0;&#xBCC0;&#xC774;&#xC758; &#xBCD1; &#xC801;&#xC778; &#xC774;&#xC0C1;&#xC774; &#xD06C;&#xAC8C; &#xC54C;&#xB824;&#xC9C0;&#xC9C0; &#xC54A;&#xC740;.&#xC785;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC; &#xC5EC;&#xAE30; Drosophila pink1&#xC758; &#xADF8; &#xBE44;&#xD65C;&#xC131;&#xD654; &#xD45C;&#xC2DC; (dPINK1)&#xB294; &#xC778;&#xAC04;&#xC758; pink1&#xC758; &#xC2DD;&#xC5D0; &#xC758;&#xD574; &#xAD6C;&#xCD9C; &#xB418; dopaminergic &#xC2E0;&#xACBD; &#xC138;&#xD3EC;&#xC758; &#xC9C4;&#xBCF4;&#xC801;&#xC778; &#xC190;&#xC2E4; &#xBC0F; ommatidial &#xBCC0;&#xC131; &#xD654;&#xD569;&#xBB3C; &#xB208;&#xC758; RNAi &#xACB0;&#xACFC; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC;, (hPINK1). &#xC778;&#xAC04;&#xC758; SOD1 &#xD45C;&#xD604;&#xC758; neurodegeneration&#xC744; dPINK1 &#xBE44;&#xD65C;&#xC131;&#xD654;&#xC5D0; &#xC758;&#xD574; &#xC720;&#xB3C4; &#xD558;&#xC9C0; &#xC54A;&#xC2B5;&#xB2C8;&#xB2E4;. &#xB610;&#xD55C;, RNAi &#xD30C;&#xB9AC; &#xB5BC;&#xC640; &#xBE44;&#xD0C0;&#xBBFC; E &#xD56D; &#xC0B0;&#xD654; &#xD06C;&#xAC8C; Dpink1&#xC758; &#xCE58;&#xB8CC; ommatidial &#xBCC0;&#xC131;&#xC744; &#xC5B5;&#xC81C; &#xD55C;&#xB2E4;. &#xB530;&#xB77C;&#xC11C;, dPINK1 &#xD568;&#xC73C;&#xB85C;&#xC368; &#xC81C;&#xC548; &#xD558;&#xB294; PINK1 &#xD568;&#xC218;&#xC5D0;&#xC11C; &#xAC10;&#xC18C; &#xB9AC;&#xB4DC; neurodegeneration PD &#xAD00;&#xB828; &#xB41C; &#xC7A0;&#xC7AC;&#xC801;&#xC778; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xACAA;&#xACE0; &#xC0B0;&#xD654; &#xC2A4;&#xD2B8;&#xB808;&#xC2A4; &#xB85C;&#xBD80;&#xD130; &#xC2E0;&#xACBD; &#xC138;&#xD3EC;&#xB97C; &#xBC29;&#xC9C0; &#xD558; &#xC5EC; &#xC2E0;&#xACBD; &#xC0DD;&#xC874; &#xC720;&#xC9C0; &#xD558;&#xB294; &#xB370; &#xD544;&#xC218;&#xC801;&#xC778; &#xC5ED;&#xD560;&#xC744; &#xD55C;&#xB2E4;.

&#xD56D; &#xC0B0;&#xD654;&#xB294; &#xCD08;&#xD30C;&#xB9AC;&#xC5D0; PINK1 &#xC885;&#xC18D; dopaminergic &#xC2E0;&#xACBD; &#xC138;&#xD3EC;&#xB97C; &#xBCF4;&#xD638;&#xD569;&#xB2C8;&#xB2E4;.

La enfermedad de Parkinson (EP) es el trastorno neurodegenerativo del movimiento m&#xE1;s frecuente. Las mutaciones en el gen PINK1 est&#xE1;n vinculados a la forma autos&#xF3;mica recesiva de aparici&#xF3;n temprana familiar de la enfermedad de Parkinson. La funci&#xF3;n fisiol&#xF3;gica de PINK1 y anomal&#xED;a patol&#xF3;gica de PD asociadas a los mutantes PINK1 son en gran parte desconocido. Estamos aqu&#xED;, muestran que la inactivaci&#xF3;n de Drosophila PINK1 (dPINK1) utilizando los resultados de RNAi en la p&#xE9;rdida progresiva de neuronas dopamin&#xE9;rgicas y en la degeneraci&#xF3;n ommatidial del ojo compuesto, que es rescatado por la expresi&#xF3;n de los derechos humanos PINK1 (hPINK1). Expresi&#xF3;n de SOD1 humana suprime la neurodegeneraci&#xF3;n inducida por dPINK1 inactivaci&#xF3;n. Por otra parte, el tratamiento de RNAi dPINK1 vuela con la SOD antioxidantes y la vitamina E inhibe significativamente la degeneraci&#xF3;n ommatidial. Por lo tanto, dPINK1 juega un papel esencial en el mantenimiento de la supervivencia neuronal mediante la prevenci&#xF3;n de las neuronas de someterse a estr&#xE9;s oxidativo, lo que sugiere un posible mecanismo por el cual una reducci&#xF3;n de la PINK1 funci&#xF3;n conduce a la neurodegeneraci&#xF3;n asociada a la EP.

Los antioxidantes protegen PINK1 dependientes de las neuronas dopamin&#xE9;rgicas en Drosophila

&#x80FD;&#x6E90;&#x9650;&#x5236;&#x589E;&#x52A0;&#x6297;&#x9006;&#x6027;&#x548C;&#x679C;&#x8747;&#x548C;&#x5176;&#x4ED6;&#x7269;&#x79CD;&#x7684;&#x5BFF;&#x547D;&#x3002;&#x5728;&#x8010;&#x5E94;&#x529B;&#x548C;&#x957F;&#x5BFF;&#x7684;&#x4E2A;&#x522B;&#x8425;&#x517B;&#x7D20;&#x7684;&#x4F5C;&#x7528;&#x662F;&#x5F88;&#x5927;&#x7A0B;&#x5EA6;&#x4E0A;&#x662F;&#x672A;&#x77E5;&#x7684;&#x3002;&#x7EF4;&#x751F;&#x7D20;&#x751F;&#x7269;&#x7D20;&#x8C03;&#x89E3;&#x8FD9;&#x4E9B;&#x5F71;&#x54CD;&#xFF0C;&#x9274;&#x4E8E;&#x5176;&#x5DF2;&#x77E5;&#x7684;&#x89D2;&#x8272;&#x5E94;&#x6FC0;&#x4FE1;&#x53F7;&#x8F6C;&#x5BFC;&#x53CA;&#x57FA;&#x56E0;&#x8C03;&#x63A7;&#x7684;&#x8868;&#x89C2;&#x9057;&#x4F20;&#x673A;&#x5236;&#xFF0C;&#x5373;&#x751F;&#x7269;&#x7D20;&#x86CB;&#x767D;&#x662F;&#x6F5C;&#x5728;&#x7684;&#x5019;&#x9009;&#x4EBA;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;&#x6211;&#x4EEC;&#x6D4B;&#x8BD5;&#x4E86;&#x8FD9;&#x4E2A;&#x5047;&#x8BBE;&#xFF0C;&#x5EF6;&#x957F;&#x679C;&#x8747;&#x751F;&#x7269;&#x7D20;&#x7F3A;&#x4E4F;&#x75C7; (BD) &#x4E2D;&#x671F;&#x589E;&#x52A0;&#x6297;&#x9006;&#x6027;&#x548C;&#x4F7F;&#x7528;&#x5BFF;&#x547D;&#x4E0A;&#x7684;&#x6587;&#x5316;&#x3002;&#x82CD;&#x8747;&#x5C4B;&#x5B87;&#x7F72;&#x996E;&#x98DF;&#x5582;&#x517B;&#x7684;&#x591A;&#x4EE3; &#xFF1B;&#x63A7;&#x4EF6;&#x88AB;&#x5582;&#x98DF;&#x751F;&#x7269;&#x7D20;&#x6B63;&#x5E38;&#x996E;&#x98DF;&#x3002;&#x5728;&#x4E00;&#x4E9B;&#x5B9E;&#x9A8C;&#x4E2D;&#xFF0C;&#x82CD;&#x8747;&#x7684;&#x7B2C;&#x4E09;&#x7EC4;&#x662F; 12 &#x4EE3;&#x5C4B;&#x5B87;&#x7F72;&#x996E;&#x98DF;&#xFF0C;&#x7136;&#x540E;&#x5207;&#x6362;&#x5230; 2 &#x4EE3;&#x6D88;&#x9664;&#x77ED;&#x671F;&#x751F;&#x7269;&#x7D20;&#x7F3A;&#x4E4F;&#x75C7;&#x7684;&#x6F5C;&#x5728;&#x5F71;&#x54CD;&#x7684;&#x63A7;&#x5236;&#x996E;&#x98DF;&#x3002;&#x82CD;&#x8747;&#x5582;&#x4EE5;&#x5C4B;&#x5B87;&#x7F72;&#x5C55;&#x51FA;&#x7684;&#x5BFF;&#x547D;&#x589E;&#x52A0;&#x4E86; 30%&#x3002;&#x8FD9;&#x79CD;&#x589E;&#x52A0;&#x662F;&#x4E0E; DNA &#x7834;&#x574F;&#x5242;&#x7F9F;&#x57FA;&#x8132;&#x548C;&#x70ED;&#x5E94;&#x529B;&#x589E;&#x5F3A;&#x6297;&#x6027;&#x76F8;&#x5173;&#x8054;&#x3002;&#x6B64;&#x5916;&#xFF0C;&#x4E0E;&#x751F;&#x7269;&#x7D20;&#x6B63;&#x5E38;&#x63A7;&#x4EF6;&#x5927;&#x5927;&#x76F8;&#x6BD4;&#xFF0C;&#x589E;&#x52A0;&#x80A5;&#x529B;&#x3002;&#x751F;&#x7269;&#x7D20;&#x86CB;&#x767D;&#x662F;&#x51E0;&#x4E4E;&#x6CA1;&#x6709;&#x5BDF;&#x89C9;&#x7684;&#x751F;&#x7269;&#x7D20;&#x5265;&#x593A;&#x82CD;&#x8747;&#xFF0C;&#x6697;&#x793A;&#x540E;&#x751F;&#x4E8B;&#x4EF6;&#x53EF;&#x80FD;&#x52A9;&#x957F;&#x4E86;&#x751F;&#x7269;&#x7D20;&#x5265;&#x593A;&#x7684;&#x5F71;&#x54CD;&#x3002;

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Energy restriction increases stress resistance and lifespan in Drosophila melanogaster and other species. The roles of individual nutrients in stress resistance and longevity are largely unknown. The vitamin biotin is a potential candidate for mediating these effects, given its known roles in stress signaling and gene regulation by epigenetic mechanisms, i.e. biotinylation of histones. Here, we tested the hypothesis that prolonged culture of Drosophila on biotin-deficient (BD) medium increases stress resistance and lifespan. Flies were fed a BD diet for multiple generations; controls were fed a biotin-normal diet. In some experiments, a third group of flies was fed a BD diet for 12 generations and then switched to control diets for 2 generations to eliminate potential effects of short-term biotin deficiency. Flies fed a BD diet exhibited a 30% increase in lifespan. This increase was associated with enhanced resistance to the DNA-damaging agent hydroxyurea and heat stress. Also, fertility increased significantly compared with biotin-normal controls. Biotinylation of histones was barely detectable in biotin-deprived flies, suggesting that epigenetic events might have contributed to effects of biotin deprivation.

Feeding Drosophila a biotin-deficient diet for multiple generations increases stress resistance and lifespan and alters gene expression and histone biotinylation patterns.

Restriction de l&#x26;#39;&#xE9;nergie augmente la r&#xE9;sistance au stress et la dur&#xE9;e de vie chez Drosophila melanogaster et d&#x26;#39;autres esp&#xE8;ces. Les r&#xF4;les des nutriments individuels dans la r&#xE9;sistance au stress et la long&#xE9;vit&#xE9; sont largement inconnues. La biotine est un candidat potentiel pour la m&#xE9;diation de ces effets, compte tenu de ses r&#xF4;les connus dans la signalisation du stress et la r&#xE9;gulation des g&#xE8;nes par des m&#xE9;canismes &#xE9;pig&#xE9;n&#xE9;tiques, c.-&#xE0;-biotinylation des histones. Ici, nous avons test&#xE9; l&#x26;#39;hypoth&#xE8;se que la culture prolong&#xE9;e de la drosophile sur la biotine-d&#xE9;ficiente (BD) &#xE0; moyen de stress augmente la r&#xE9;sistance et de dur&#xE9;e de vie. Les mouches ont &#xE9;t&#xE9; nourris avec un r&#xE9;gime BD pour de multiples g&#xE9;n&#xE9;rations, les contr&#xF4;les ont &#xE9;t&#xE9; nourris avec un r&#xE9;gime biotine-normale. Dans certaines exp&#xE9;riences, un troisi&#xE8;me groupe de mouches a &#xE9;t&#xE9; nourris avec un r&#xE9;gime BD pour 12 g&#xE9;n&#xE9;rations et sont ensuite pass&#xE9;s &#xE0; contr&#xF4;ler les r&#xE9;gimes de 2 g&#xE9;n&#xE9;rations pour &#xE9;liminer les effets potentiels d&#x26;#39;une carence en biotine &#xE0; court terme. Mouches nourris avec un r&#xE9;gime BD montr&#xE9; une augmentation de 30% en dur&#xE9;e de vie. Cette augmentation a &#xE9;t&#xE9; associ&#xE9;e &#xE0; une r&#xE9;sistance accrue &#xE0; l&#x26;#39;agent endommageant l&#x26;#39;ADN hydroxyur&#xE9;e et le stress de chaleur. En outre, la f&#xE9;condit&#xE9; a augment&#xE9; significativement par rapport &#xE0; la biotine &#xE0; la normale des contr&#xF4;les. Biotinylation des histones &#xE9;tait &#xE0; peine d&#xE9;tectable chez les mouches biotine-priv&#xE9;s, ce qui sugg&#xE8;re que les &#xE9;v&#xE9;nements &#xE9;pig&#xE9;n&#xE9;tiques pourraient avoir contribu&#xE9; aux effets de la privation de biotine.

Nourrir la drosophile une di&#xE8;te d&#xE9;ficiente en biotine pour les g&#xE9;n&#xE9;rations multiples Augmente la r&#xE9;sistance au stress et l&#x26;#39;expression g&#xE9;nique dur&#xE9;e de vie et qui modifie Patterns biotinylation histones

Energie-Beschr&auml;nkung erh&ouml;ht Stressresistenz und Lebensdauer in Drosophila Melanogaster und andere Arten. Die Rollen der einzelnen N&auml;hrstoffe in Belastbarkeit und Langlebigkeit sind weitgehend unbekannt. Das Vitamin Biotin ist ein m&ouml;glicher Kandidat f&uuml;r die Vermittlung dieser Effekte, seine bekannten Rollen in Stress-Signalisierung und gen-Verordnung von epigenetischen Mechanismen, d.h. Biotinylierung des Histone gegeben. Hier haben wir die Hypothese, die Kultur von Drosophila auf Biotin-Mangel (BD) mittlere erh&ouml;ht Stressresistenz und Lebensdauer verl&auml;ngert getestet. Fliegen waren seit mehreren Generationen eine BD-Di&auml;t gef&uuml;ttert; Steuerelemente wurden eine Biotin-Normal-Di&auml;t gef&uuml;ttert. In vielen Experimenten war eine dritte Gruppe von fliegen eine BD-Di&auml;t f&uuml;r 12 Generationen gef&uuml;ttert und wechselte dann auf Steuerelement-Di&auml;ten f&uuml;r 2 Generationen, m&ouml;gliche Auswirkungen der kurzfristigen Biotin-Mangel zu beseitigen. Fliegt eine BD-Ern&auml;hrung gespeist stellte eine Erh&ouml;hung der Lebensdauer 30 %. Dieser Anstieg war erh&ouml;hte Resistenz gegen die DNA-sch&auml;digenden Agent Hydroxyurea und Hitze Stress zugeordnet. Au&szlig;erdem stieg die Fruchtbarkeit deutlich im Vergleich Biotin-Normal-Steuerelemente. Biotinylierung des Histone war kaum wahrnehmbar in Biotin-beraubt fliegen, was darauf hindeutet, dass epigenetische Ereignisse zu Wirkungen von Biotin Deprivation beigetragen haben k&ouml;nnte.

F&uuml;tterung von Drosophila eine Biotin-Mangel-Ern&auml;hrung f&uuml;r mehrere Generationen erh&ouml;ht die Belastbarkeit und Lebensdauer und ver&auml;ndert Genexpression und Histon Biotinylierung Muster.

Limitazione di energia aumenta la resistenza e durata in Drosophila melanogaster e di altre specie. I ruoli dei singoli nutrienti nella resistenza e longevit&agrave; sono in gran parte sconosciuti. La biotina vitamina &egrave; un potenziale candidato per mediare questi effetti, dato i relativi ruoli noti nel regolamento segnalazione e gene lo stress da meccanismi epigenetici, cio&egrave; biotinylation di istoni. Qui, abbiamo testato l&#39;ipotesi che la prolungata coltura della drosofila sul deficit di biotina (BD) medio aumenta resistenza e durata. Mosche erano alimentati una dieta BD per pi&ugrave; generazioni; i controlli sono stati alimentati una dieta normale di biotina. In alcuni esperimenti, un terzo gruppo di mosche &egrave; stato alimentato una dieta BD per 12 generazioni e poi passato al controllo diete per 2 generazioni eliminare potenziali effetti di breve termine deficit di biotina. Mosche alimentati una dieta BD esibito un aumento del 30% nella durata della vita. Questo aumento &egrave; stato associato con una maggiore resistenza allo danneggiando DNA agente hydroxyurea e calore sforzo. Inoltre, fertilit&agrave; aumentata significativamente rispetto ai controlli normali di biotina. Biotinylation di istoni era a malapena rilevabili in biotina-privato mosche, suggerendo che gli eventi epigenetici potrebbero aver contribuito agli effetti di privazione di biotina.

Alimentazione Drosophila una dieta carente di biotina per pi&ugrave; generazioni aumenta la resistenza e la durata della vita e altera l&#39;espressione del gene e dell&#39;istone biotinylation modelli.

&#x30A8;&#x30CD;&#x30EB;&#x30AE;&#x30FC;&#x5236;&#x9650;&#x306F;&#x3001;&#x30AD;&#x30A4;&#x30ED;&#x30B7;&#x30E7;&#x30A6;&#x30B8;&#x30E7;&#x30A6;&#x30D0;&#x30A8;&#x3084;&#x4ED6;&#x306E;&#x7A2E;&#x306B;&#x304A;&#x3051;&#x308B;&#x30B9;&#x30C8;&#x30EC;&#x30B9;&#x8010;&#x6027;&#x3068;&#x5BFF;&#x547D;&#x3092;&#x5411;&#x4E0A;&#x3055;&#x305B;&#x307E;&#x3059;&#x3002;&#x30B9;&#x30C8;&#x30EC;&#x30B9;&#x62B5;&#x6297;&#x6027;&#x3068;&#x5BFF;&#x547D;&#x306E;&#x500B;&#x3005;&#x306E;&#x6804;&#x990A;&#x7D20;&#x306E;&#x5F79;&#x5272;&#x306F;&#x4E0D;&#x660E;&#x306A;&#x70B9;&#x304C;&#x591A;&#x3044;&#x3002;&#x30D3;&#x30BF;&#x30DF;&#x30F3;&#x30D3;&#x30AA;&#x30C1;&#x30F3;&#x306F;&#x3001;&#x30A8;&#x30D4;&#x30B8;&#x30A7;&#x30CD;&#x30C6;&#x30A3;&#x30C3;&#x30AF;&#x306A;&#x6A5F;&#x69CB;&#x3001;&#x30D2;&#x30B9;&#x30C8;&#x30F3;&#x3059;&#x306A;&#x308F;&#x3061;&#x30D3;&#x30AA;&#x30C1;&#x30F3;&#x5316;&#x306B;&#x3088;&#x308B;&#x5FDC;&#x529B;&#x4F1D;&#x9054;&#x3068;&#x907A;&#x4F1D;&#x5B50;&#x8ABF;&#x7BC0;&#x306B;&#x304A;&#x3051;&#x308B;&#x305D;&#x306E;&#x77E5;&#x3089;&#x308C;&#x3066;&#x3044;&#x308B;&#x5F79;&#x5272;&#x3092;&#x4E0E;&#x3048;&#x3089;&#x308C;&#x305F;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;&#x52B9;&#x679C;&#x3092;&#x4EF2;&#x4ECB;&#x3059;&#x308B;&#x305F;&#x3081;&#x306E;&#x6F5C;&#x5728;&#x7684;&#x306A;&#x5019;&#x88DC;&#x3067;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;&#x4EEE;&#x8AAC;&#x3092;&#x691C;&#x8A3C;&#x3057;&#x3001;&#x305D;&#x306E;&#x30D3;&#x30AA;&#x30C1;&#x30F3;&#x6B20;&#x4E4F;&#xFF08;BD&#xFF09;&#x30E1;&#x30C7;&#x30A3;&#x30A2;&#x306E;&#x5897;&#x52A0;&#x3001;&#x30B9;&#x30C8;&#x30EC;&#x30B9;&#x62B5;&#x6297;&#x6027;&#x3068;&#x5BFF;&#x547D;&#x306B;&#x30B7;&#x30E7;&#x30A6;&#x30B8;&#x30E7;&#x30A6;&#x30D0;&#x30A8;&#x306E;&#x9577;&#x671F;&#x57F9;&#x990A;&#x3002;&#x30CF;&#x30A8;&#x306F;&#x3001;&#x8907;&#x6570;&#x306E;&#x4E16;&#x4EE3;&#x306E;BD&#x98FC;&#x6599;&#x3092;&#x4E0E;&#x3048;&#x305F;&#x3002;&#x30B3;&#x30F3;&#x30C8;&#x30ED;&#x30FC;&#x30EB;&#x306F;&#x3001;&#x30D3;&#x30AA;&#x30C1;&#x30F3;&#x3001;&#x901A;&#x5E38;&#x306E;&#x98FC;&#x6599;&#x3092;&#x4E0E;&#x3048;&#x305F;&#x3002;&#x3044;&#x304F;&#x3064;&#x304B;&#x306E;&#x5B9F;&#x9A13;&#x3067;&#x306F;&#x3001;&#x30CF;&#x30A8;&#x306E;&#x7B2C;&#x4E09;&#x306E;&#x30B0;&#x30EB;&#x30FC;&#x30D7;&#x306F;&#x3001;12&#x4E16;&#x4EE3;&#x306E;&#x305F;&#x3081;&#x306B;BD&#x306E;&#x98FC;&#x6599;&#x3092;&#x4E0E;&#x3048;&#x3001;&#x305D;&#x306E;&#x5F8C;&#x3001;&#x77ED;&#x671F;&#x7684;&#x306A;&#x30D3;&#x30AA;&#x30C1;&#x30F3;&#x6B20;&#x4E4F;&#x306E;&#x6F5C;&#x5728;&#x7684;&#x306A;&#x5F71;&#x97FF;&#x3092;&#x6392;&#x9664;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;2&#x4E16;&#x4EE3;&#x7528;&#x98FC;&#x6599;&#x3092;&#x5236;&#x5FA1;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x5207;&#x308A;&#x66FF;&#x3048;&#x305F;&#x3002; FRB&#x306F;BD&#x306E;&#x98DF;&#x4E8B;&#x306F;&#x5BFF;&#x547D;&#x306E;30&#xFF05;&#x5897;&#x3092;&#x793A;&#x3057;&#x305F;&#x98DB;&#x3076;&#x3002;&#x3053;&#x306E;&#x5897;&#x52A0;&#x306F;&#x3001;DNA&#x640D;&#x50B7;&#x5264;&#x30D2;&#x30C9;&#x30ED;&#x30AD;&#x30B7;&#x30A6;&#x30EC;&#x30A2;&#x3068;&#x71B1;&#x5FDC;&#x529B;&#x306B;&#x5F37;&#x5316;&#x3055;&#x308C;&#x305F;&#x62B5;&#x6297;&#x6027;&#x3068;&#x95A2;&#x9023;&#x3057;&#x3066;&#x3044;&#x305F;&#x3002;&#x307E;&#x305F;&#x3001;&#x51FA;&#x751F;&#x7387;&#x304C;&#x30D3;&#x30AA;&#x30C1;&#x30F3; - &#x6B63;&#x5E38;&#x5BFE;&#x7167;&#x7FA4;&#x3068;&#x6BD4;&#x8F03;&#x3057;&#x3066;&#x6709;&#x610F;&#x306B;&#x5897;&#x52A0;&#x3057;&#x305F;&#x3002;&#x30D2;&#x30B9;&#x30C8;&#x30F3;&#x306E;&#x30D3;&#x30AA;&#x30C1;&#x30F3;&#x5316;&#x306F;&#x3001;&#x30A8;&#x30D4;&#x30B8;&#x30A7;&#x30CD;&#x30C6;&#x30A3;&#x30C3;&#x30AF;&#x306A;&#x30A4;&#x30D9;&#x30F3;&#x30C8;&#x304C;&#x30D3;&#x30AA;&#x30C1;&#x30F3;&#x6B20;&#x4E4F;&#x306E;&#x5F71;&#x97FF;&#x306B;&#x8CA2;&#x732E;&#x3057;&#x3066;&#x3044;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x308B;&#x3001;&#x30D3;&#x30AA;&#x30C1;&#x30F3;&#x304C;&#x596A;&#x308F;&#x308C;&#x305F;&#x30CF;&#x30A8;&#x3067;&#x304B;&#x308D;&#x3046;&#x3058;&#x3066;&#x691C;&#x51FA;&#x53EF;&#x80FD;&#x3067;&#x3042;&#x3063;&#x305F;&#x3002;

&#x30B7;&#x30E7;&#x30A6;&#x30B8;&#x30E7;&#x30A6;&#x30D0;&#x30A8;&#x3092;&#x4F9B;&#x7D66;&#x3059;&#x308B;&#x8907;&#x6570;&#x306E;&#x4E16;&#x4EE3;&#x306E;&#x305F;&#x3081;&#x306E;&#x30D3;&#x30AA;&#x30C1;&#x30F3;&#x6B20;&#x4E4F;&#x98DF;&#x3067;&#x306F;&#x3001;&#x30B9;&#x30C8;&#x30EC;&#x30B9;&#x62B5;&#x6297;&#x6027;&#x3068;&#x5BFF;&#x547D;&#x3068;&#x3092;&#x5909;&#x5316;&#x3055;&#x305B;&#x308B;&#x907A;&#x4F1D;&#x5B50;&#x767A;&#x73FE;&#x3068;&#x30D2;&#x30B9;&#x30C8;&#x30F3;&#x30D3;&#x30AA;&#x30C1;&#x30F3;&#x5316;&#x30D1;&#x30BF;&#x30FC;&#x30F3;&#x3092;&#x5897;&#x52A0;&#x3055;&#x305B;&#x308B;

&#xC5D0;&#xB108;&#xC9C0; &#xC81C;&#xD55C; &#xC99D;&#xAC00; &#xC2A4;&#xD2B8;&#xB808;&#xC2A4; &#xC800;&#xD56D;&#xACFC; &#xC218;&#xBA85; Drosophila melanogaster&#xC640; &#xB2E4;&#xB978; &#xC218; &#xC885;&#xC5D0;. &#xC2A4;&#xD2B8;&#xB808;&#xC2A4; &#xC800;&#xD56D;&#xACFC; &#xC218;&#xBA85;&#xC5D0; &#xAC1C;&#xBCC4; &#xC601;&#xC591;&#xC18C;&#xC758; &#xC5ED;&#xD560;&#xC740; &#xD06C;&#xAC8C; &#xC54C;&#xB824;&#xC9C0;&#xC9C0; &#xC54A;&#xC740;.&#xC785;&#xB2C8;&#xB2E4;. &#xBE44;&#xD0C0;&#xBBFC; biotin epigenetic &#xBA54;&#xCEE4;&#xB2C8;&#xC998;, &#xC989;, &#xD788;&#xC2A4;&#xD1A4;&#xC758; biotinylation&#xC5D0; &#xC758;&#xD574; &#xADF8;&#xAC83;&#xC758; &#xC54C;&#xB824;&#xC9C4;&#xB41C; &#xC5ED;&#xD560; &#xC2A4;&#xD2B8;&#xB808;&#xC2A4; &#xC2E0;&#xD638; &#xBC0F; &#xC720;&#xC804;&#xC790; &#xADDC;&#xC815;&#xC5D0; &#xC8FC;&#xC5B4;&#xC9C4; &#xC774;&#xB7EC;&#xD55C; &#xD6A8;&#xACFC; &#xC911;&#xC7AC; &#xD558;&#xB294; &#xAC83;&#xC5D0; &#xB300; &#xD55C; &#xC7A0;&#xC7AC;&#xC801;&#xC778; &#xD6C4;&#xBCF4;&#xC785;&#xB2C8;&#xB2E4;. &#xC5EC;&#xAE30;, &#xC6B0;&#xB9AC; &#xBB38;&#xD654; &#xCD08;&#xD30C;&#xB9AC;&#xC758; &#xBE44;&#xC624; &#xD2F4; &#xACB0;&#xD54D; (BD) &#xC911;&#xAC04; &#xC99D;&#xAC00; &#xC2A4;&#xD2B8;&#xB808;&#xC2A4; &#xC800;&#xD56D;&#xACFC; &#xC218;&#xBA85;&#xC5D0; &#xC5F0;&#xC7A5; &#xAC00;&#xC124; &#xD14C;&#xC2A4;&#xD2B8;. &#xD30C;&#xB9AC; &#xC5EC;&#xB7EC; &#xC138;&#xB300;; BD &#xB2E4;&#xC774;&#xC5B4;&#xD2B8; &#xC9C0; &#xB8E8; &#xD588;&#xB2E4; &#xCEE8;&#xD2B8;&#xB864; biotin &#xC77C;&#xBC18; &#xB2E4;&#xC774;&#xC5B4;&#xD2B8; &#xC9C0; &#xB8E8; &#xD588;&#xB2E4;. &#xC77C;&#xBD80; &#xC2E4;&#xD5D8; &#xD30C;&#xB9AC;&#xC758; &#xC138; &#xBC88;&#xC9F8; &#xADF8;&#xB8F9; 12 &#xC138;&#xB300; BD &#xB2E4;&#xC774;&#xC5B4;&#xD2B8;&#xB97C; &#xBA39;&#xC774; &#xB418;&#xC5C8;&#xACE0; &#xB2E8;&#xAE30; &#xBE44;&#xC624; &#xD2F4; &#xACB0;&#xD54D;&#xC758; &#xC7A0;&#xC7AC;&#xC801;&#xC778; &#xD6A8;&#xACFC; &#xC81C;&#xAC70; &#xD558;&#xAE30; &#xC704;&#xD574; 2 &#xC138;&#xB300;&#xC5D0; &#xB300; &#xD55C; &#xC81C;&#xC5B4; &#xB2E4;&#xC774;&#xC5B4;&#xD2B8; &#xB2E4;&#xC74C; &#xC804;&#xD658;. BD &#xB2E4;&#xC774;&#xC5B4;&#xD2B8;&#xB97C; &#xBA39;&#xC774; &#xD558;&#xB294; &#xD30C;&#xB9AC; &#xC804;&#xC2DC; &#xC218;&#xBA85; 30% &#xC99D;&#xAC00;. &#xC774; &#xC99D;&#xAC00; DNA &#xC190;&#xC0C1; &#xC5D0;&#xC774;&#xC804;&#xD2B8; hydroxyurea&#xC640; &#xC5F4; &#xC2A4;&#xD2B8;&#xB808;&#xC2A4;&#xC5D0; &#xB300; &#xD55C; &#xD5A5;&#xC0C1; &#xB41C; &#xC800;&#xD56D;&#xC5D0; &#xC5F0;&#xACB0; &#xD588;&#xB2E4;. &#xB610;&#xD55C;, &#xB2E4; &#xC0B0; biotin &#xC815;&#xC0C1; &#xCEE8;&#xD2B8;&#xB864;&#xC5D0; &#xBE44;&#xD574; &#xD06C;&#xAC8C; &#xC99D;&#xAC00; &#xD588;&#xB2E4;. &#xD788;&#xC2A4;&#xD1A4;&#xC758; Biotinylation biotin&#xC744; &#xBC15;&#xD0C8; &#xD30C;&#xB9AC;&#xC5D0;&#xC11C; &#xAC70;&#xC758; &#xAC10;&#xC9C0; epigenetic &#xC774;&#xBCA4;&#xD2B8; biotin &#xBD80;&#xC871;&#xC758; &#xD6A8;&#xACFC;&#xC5D0; &#xAE30;&#xC5EC; &#xD560; &#xC218;&#xB3C4; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4; &#xC81C;&#xC548; &#xD588;&#xB2E4;.

&#xC5EC;&#xB7EC; &#xC138;&#xB300;&#xC5D0; &#xB300; &#xD55C; &#xBD88;&#xCDA9;&#xBD84; &#xD55C; biotin &#xB2E4;&#xC774;&#xC5B4;&#xD2B8; &#xCD08;&#xD30C;&#xB9AC; &#xBA39;&#xC774; &#xC2A4;&#xD2B8;&#xB808;&#xC2A4; &#xC800;&#xD56D;&#xACFC; &#xC218;&#xBA85; &#xC99D;&#xAC00; &#xBC0F; &#xC720;&#xC804;&#xC790; &#xBC1C;&#xD604; &#xBC0F; &#xD788;&#xC2A4;&#xD1A4; biotinylation &#xD328;&#xD134; &#xBCC0;&#xACBD;.

La restricci&#xF3;n de energ&#xED;a aumenta la resistencia al estr&#xE9;s y la vida en la Drosophila melanogaster y otras especies. Las funciones de los nutrientes individuales en la resistencia al estr&#xE9;s y la longevidad son en gran parte desconocido. La vitamina biotina es un potencial candidato para mediar estos efectos, dadas sus funciones conocidas en la se&#xF1;alizaci&#xF3;n de estr&#xE9;s y la regulaci&#xF3;n de genes por mecanismos epigen&#xE9;ticos, es decir, biotinilaci&#xF3;n de las histonas. En este caso, hemos probado la hip&#xF3;tesis de que el cultivo prolongado de Drosophila en la deficiencia de biotina (BD), la resistencia aumenta el estr&#xE9;s y el medio de vida. Las moscas fueron alimentados con una dieta de BD para varias generaciones, los controles fueron alimentados con una dieta con biotina normal. En algunos experimentos, un tercer grupo de moscas fue alimentado con una dieta BD durante 12 generaciones y luego cambi&#xF3; a controlar las dietas para 2 generaciones para eliminar los efectos potenciales de la deficiencia de biotina a corto plazo. Las moscas alimentadas con una dieta BD mostraron un aumento del 30% en el per&#xED;odo de vida. Este aumento se asoci&#xF3; con una mayor resistencia a la agente hidroxiurea que da&#xF1;an el ADN y el estr&#xE9;s por calor. Adem&#xE1;s, la fertilidad aument&#xF3; significativamente en comparaci&#xF3;n con biotina-controles normales. Biotinilaci&#xF3;n de las histonas fue apenas detectable en las moscas de la biotina-privadas, lo que sugiere que los eventos epigen&#xE9;ticos podr&#xED;an haber contribuido a los efectos de la privaci&#xF3;n de la biotina.

La alimentaci&#xF3;n de Drosophila una dieta deficiente en biotina para las generaciones m&#xFA;ltiples aumenta la resistencia al estr&#xE9;s y la expresi&#xF3;n de Lifespan y altera los patrones de genes y las histonas biotinilaci&#xF3;n

Correct differentiation and positioning of individual synapses during development is fundamental to the normal function of neuronal circuits. While classical transmitters such as serotonin (5-HT) play a critical trophic role in neurogenesis in addition to their functions as transmitters in the mature nervous system, this process is not well understood. We used a simple model to assess both development and function of a specific behavioral circuit in the larval stage of the fruit fly (Drosophila melanogaster). We show that, as in all other species examined, the neurotransmitter actions of 5-HT depress feeding, and decreased neuronal 5-HT levels increase appetite. However, using transgenic tools, we show that constitutive knockdown of neuronal 5-HT synthesis to reduce 5-HT levels during central nervous system (CNS) development results in increased branching of the serotonergic fibers projecting to the gut, as well as increased size and number of varicosities along the neurite length. As larvae, these animals display decreased feeding rates relative to controls, and, when given exogenous 5-hydroxytryptophan, feeding is significantly enhanced. Late-stage wild-type embryos exposed to 5-HT to augment 5-HT levels during CNS development display, as mature larvae, a significant decrease in gut fiber branching and total varicosity number, as well as increased feeding and a hyposensitivity to the effects of 5-HT. Exposure of embryos unable to synthesize neuronal serotonin to 5-HT during late embryogenesis results in rescue of the feeding behavior and abnormalities in the 5-HT gut fiber architecture. These results demonstrate an inverse relationship between developmental 5-HT levels and complexity of the fiber architecture projecting to gut tissue, which results in a perturbed feeding pattern. We conclude that 5-HT is tightly regulated during CNS development to direct the normal architecture and mature function of this neural circuit.

A trophic role for serotonin in the development of a simple feeding circuit.

In the fruit fly, Drosophila melanogaster, serotonin functions both as a neurotransmitter to regulate larval feeding, and in the development of the stomatogastric feeding circuit. There is an inverse relationship between neuronal serotonin levels during late embryogenesis and the complexity of the serotonergic fibers projecting from the larval brain to the foregut, which correlate with perturbations in feeding, the functional output of the circuit. Dopamine does not modulate larval feeding, and dopaminergic fibers do not innervate the larval foregut. Since dopamine can function in central nervous system development, separate from its role as a neurotransmitter, the role of neuronal dopamine was assessed on the development, and mature function, of the 5-HT larval feeding circuit.

Neurotrophic actions of dopamine on the development of a serotonergic feeding circuit in Drosophila melanogaster.

Numerous studies have detailed the extensive conservation of developmental signaling pathways between the model system, Drosophila melanogaster, and mammalian models, but researchers have also profited from the unique and highly tractable genetic tools available in this system to address critical questions in physiology. In this review, we have described contributions that Drosophila researchers have made to mathematical dynamics of pattern formation, cardiac pathologies, the way in which pain circuits are integrated to elicit responses from sensation, as well as the ways in which gene expression can modulate diverse behaviors and shed light on human cognitive disorders. The broad and diverse array of contributions from Drosophila underscore its translational relevance to modeling human disease.

Comparative approaches to the study of physiology: Drosophila as a physiological tool.

Many studies have pointed to vulnerability to stress and stress-related pathologies at different timepoints during an individual's life span. These sensitive windows are usually during periods of neural development, such as embryogenesis, infancy, and adolescence. It is critical to understand how neural circuitry may change as an individual ages in ways that could affect susceptibility to stress. Here we compare two stages in Drosophila melanogaster: sexual immaturity and sexual maturity. We used the genetic resources available in Drosophila to manipulate pre- and postsynaptic dopamine signaling in sexually immature and mature animals that were then assayed for heart rate and locomotor behavior in response to starvation and oxidative stress. Our results show significant differences in the stress response for sexually immature and mature animals for heart rate, periods of high mobility, mean velocity, and several other parameters of locomotor behavior. Our data show that dopamine neurons are differentially recruited into the stress response circuitry for sexually immature and mature individuals. By observing behaviors that have been previously shown in mammalian models to be affected by stress and altered in models of affective disorders, we provide a genetically tractable model for development and maintenance of the stress response circuitry during sexual maturation. (PsycINFO Database Record (c) 2013 APA, all rights reserved).

Temporally dimorphic recruitment of dopamine neurons into stress response circuitry in Drosophila.

Hormones are critical for the development, maturation, and maintenance of physiological systems; therefore, understanding their involvement during maturation of the brain is important for the elucidation of mechanisms by which adults become behaviorally competent. Changes in exogenous and endogenous factors encountered during sexual maturation can have long lasting effects in mature adults. In this study, we investigated the role of the gonadotropic hormone, juvenile hormone (JH), in the modulation of adult behaviors in Drosophila. Here we utilized methoprene (a synthetic JH analog) and precocene (a JH synthesis inhibitor) to manipulate levels of JH in sexually immature male and female Drosophila with or without decreased synthesis of neuronal dopamine (DA). Locomotion and courtship behavior were assayed once the animals had grown to sexual maturity. The results demonstrate a sexually dimorphic role for JH in the modulation of these centrally controlled behaviors in mature animals that is dependent on the age of the animals assayed, and present DA as a candidate neuronal factor that differentially interacts with JH depending on the sex of the animal. The data also suggest that JH modulates these behaviors through an indirect mechanism. Since gonadotropic hormones and DA interact in mammals to affect brain development and later function, our results suggest that this mechanism for the development of adult behavioral competence may be evolutionarily conserved.

Early manipulation of juvenile hormone has sexually dimorphic effects on mature adult behavior in Drosophila melanogaster.

Several previous studies in mammalian systems have shown sexually dimorphic behaviors, neuroendocrine changes, and alterations in neurotransmitter release in response to stress. In addition, men and women are differentially vulnerable to stress-related pathologies, which have led to the hypothesis that the stress response circuitry differs depending on sex. The authors used the genetic tractability of Drosophila to manipulate pre- or postsynaptic dopamine signaling in transgenic animals, which were assayed for several parameters of locomotion and heart rate following exposure to 2 environmental stressors: starvation and oxidative stress. Their results show significant differences in the stress response for males and females by analyzing heart rate, centering time, and high mobility in addition to other locomotor parameters with translational relevance. These data demonstrate that both pre- and postsynaptic neurons are differentially recruited into the dopaminergic stress response circuitry for males and females. The results also show that the response circuits differ depending on the stressor and behavioral output. Furthermore, the authors' studies provide a translatable Drosophila model for further elucidation of factors involved in the sexually dimorphic recruitment of neurons into the stress response circuitry. (PsycINFO Database Record (c) 2013 APA, all rights reserved).

Article	Year
Pharmacological evidence for GABAergic regulation of specific behaviors in Drosophila melanogaster. Journal of neurobiology\| PubMed ID: 11810639	2002
Talking the talk: the role of VEGF proteins in cell signaling. Trends in endocrinology and metabolism: TEM\| PubMed ID: 12217482	2002
GABAergic modulation of motor-driven behaviors in juvenile Drosophila and evidence for a nonbehavioral role for GABA transport. Journal of neurobiology\| PubMed ID: 15389689	2004
Substrate regulation of serotonin and dopamine synthesis in Drosophila. Invertebrate neuroscience : IN\| PubMed ID: 15480914	2004
Serotonin synthesis by two distinct enzymes in Drosophila melanogaster. Archives of insect biochemistry and physiology\| PubMed ID: 15822093	2005
Stress affects dopaminergic signaling pathways in Drosophila melanogaster. Stress (Amsterdam, Netherlands)\| PubMed ID: 16019603	2005
Biochemical conservation of recombinant Drosophila tyrosine hydroxylase with its mammalian cognates. Biochemical genetics\| PubMed ID: 16187166	2005
Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 16938835	2006
Feeding Drosophila a biotin-deficient diet for multiple generations increases stress resistance and lifespan and alters gene expression and histone biotinylation patterns. The Journal of nutrition\| PubMed ID: 17709434	2007
A trophic role for serotonin in the development of a simple feeding circuit. Developmental neuroscience\| PubMed ID: 20714156	2010
Neurotrophic actions of dopamine on the development of a serotonergic feeding circuit in Drosophila melanogaster. BMC neuroscience\| PubMed ID: 22413901	2012
Comparative approaches to the study of physiology: Drosophila as a physiological tool. American journal of physiology. Regulatory, integrative and comparative physiology\| PubMed ID: 23220476	2013
Temporally dimorphic recruitment of dopamine neurons into stress response circuitry in Drosophila. Behavioral neuroscience\| PubMed ID: 23895060	2013
Early manipulation of juvenile hormone has sexually dimorphic effects on mature adult behavior in Drosophila melanogaster. Hormones and behavior\| PubMed ID: 24012944	2013
Sexually dimorphic recruitment of dopamine neurons into the stress response circuitry. Behavioral neuroscience\| PubMed ID: 24128361	2013

Wendi S. Neckameyer

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