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1.
Biochemistry (Mosc) ; 89(3): 393-406, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38648760

RESUMO

Courtship suppression is a behavioral adaptation of the fruit fly. When majority of the females in a fly population are fertilized and non-receptive for mating, a male, after a series of failed attempts, decreases its courtship activity towards all females, saving its energy and reproductive resources. The time of courtship decrease depends on both duration of unsuccessful courtship and genetically determined features of the male nervous system. Thereby, courtship suppression paradigm can be used for studying molecular mechanisms of learning and memory. p-Cofilin, a component of the actin remodeling signaling cascade and product of LIM-kinase 1 (LIMK1), regulates Drosophila melanogaster forgetting in olfactory learning paradigm. Previously, we have shown that limk1 suppression in the specific types of nervous cells differently affects fly courtship memory. Here, we used Gal4 > UAS system to induce limk1 overexpression in the same types of neurons. limk1 activation in the mushroom body, glia, and fruitless neurons decreased learning index compared to the control strain or the strain with limk1 knockdown. In cholinergic and dopaminergic/serotoninergic neurons, both overexpression and knockdown of limk1 impaired Drosophila short-term memory. Thus, proper balance of the limk1 activity is crucial for normal cognitive activity of the fruit fly.


Assuntos
Corte , Proteínas de Drosophila , Drosophila melanogaster , Quinases Lim , Memória , Animais , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Drosophila melanogaster/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Masculino , Quinases Lim/metabolismo , Quinases Lim/genética , Feminino , Corpos Pedunculados/metabolismo , Corpos Pedunculados/fisiologia , Comportamento Sexual Animal
2.
Cells ; 12(13)2023 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-37443751

RESUMO

Intracellular trafficking plays a critical role in the functioning of highly polarized cells, such as neurons. Transport of mRNAs, proteins, and other molecules to synaptic terminals maintains contact between neurons and ensures the transmission of nerve impulses. Cytoplasmic polyadenylation element binding (CPEB) proteins play an essential role in long-term memory (LTM) formation by regulating local translation in synapses. Here, we show that the 3'UTR of the Drosophila CPEB gene orb2 is required for targeting the orb2 mRNA and protein to synapses and that this localization is important for LTM formation. When the orb2 3'UTR is deleted, the orb2 mRNAs and proteins fail to localize in synaptic fractions, and pronounced LTM deficits arise. We found that the phenotypic effects of the orb2 3'UTR deletion were rescued by introducing the 3'UTR from the orb, another Drosophila CPEB gene. In contrast, the phenotypic effects of the 3'UTR deletion were not rescued by the 3'UTR from one of the Drosophila α-tubulin genes. Our results show that the orb2 mRNAs must be targeted to the correct locations in neurons and that proper targeting depends upon sequences in the 3'UTR.


Assuntos
Proteínas de Transporte , Proteínas de Drosophila , Animais , Proteínas de Transporte/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Regiões 3' não Traduzidas/genética , Fatores de Poliadenilação e Clivagem de mRNA/genética , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Poliadenilação/genética , Drosophila/genética , Drosophila/metabolismo , Neurônios/metabolismo
3.
Cells ; 12(2)2023 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-36672258

RESUMO

Activation of local translation in neurites in response to stimulation is an important step in the formation of long-term memory (LTM). CPEB proteins are a family of translation factors involved in LTM formation. The Drosophila CPEB protein Orb2 plays an important role in the development and function of the nervous system. Mutations of the coding region of the orb2 gene have previously been shown to impair LTM formation. We found that a deletion of the 3'UTR of the orb2 gene similarly results in loss of LTM in Drosophila. As a result of the deletion, the content of the Orb2 protein remained the same in the neuron soma, but significantly decreased in synapses. Using RNA immunoprecipitation followed by high-throughput sequencing, we detected more than 6000 potential Orb2 mRNA targets expressed in the Drosophila brain. Importantly, deletion of the 3'UTR of orb2 mRNA also affected the localization of the Csp, Pyd, and Eya proteins, which are encoded by putative mRNA targets of Orb2. Therefore, the 3'UTR of the orb2 mRNA is important for the proper localization of Orb2 and other proteins in synapses of neurons and the brain as a whole, providing a molecular basis for LTM formation.


Assuntos
Proteínas de Drosophila , Drosophila , Animais , Drosophila/metabolismo , Regiões 3' não Traduzidas/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Memória de Longo Prazo/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Junções Íntimas/metabolismo
4.
Int J Mol Sci ; 23(20)2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36293213

RESUMO

Being involved in development of Huntington's, Parkinson's and Alzheimer's diseases, kynurenine pathway (KP) of tryptophan metabolism plays a significant role in modulation of neuropathology. Accumulation of a prooxidant 3-hydroxykynurenine (3-HOK) leads to oxidative stress and neuronal cell apoptosis. Drosophila mutant cardinal (cd1) with 3-HOK excess shows age-dependent neurodegeneration and short-term memory impairments, thereby presenting a model for senile dementia. Although cd gene for phenoxazinone synthase (PHS) catalyzing 3-HOK dimerization has been presumed to harbor the cd1 mutation, its molecular nature remained obscure. Using next generation sequencing, we have shown that the cd gene in cd1 carries a long deletion leading to PHS active site destruction. Contrary to the wild type Canton-S (CS), cd1 males showed defective long-term memory (LTM) in conditioned courtship suppression paradigm (CCSP) at days 5-29 after eclosion. The number of dopaminergic neurons (DAN) regulating fly locomotor activity showed an age-dependent tendency to decrease in cd1 relative to CS. Thus, in accordance with the concept "from the gene to behavior" proclaimed by S. Benzer, we have shown that the aberrant PHS sequence in cd1 provokes drastic LTM impairments and DAN alterations.


Assuntos
Proteínas de Drosophila , Drosophila , Animais , Masculino , Drosophila/metabolismo , Cinurenina/metabolismo , Triptofano/metabolismo , Domínio Catalítico , Memória de Longo Prazo , Mutação , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo
5.
Mol Neurobiol ; 59(3): 1862-1871, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35029786

RESUMO

Kynurenine products of tryptophan metabolism are modifiers of the nervous activity and oxidative processes in mammals and invertebrates. 3-Hydroxykynurenine (3HOK) in moderate concentrations is a lipid peroxidation inhibitor. However, its accumulation and oxidative auto-dimerization lead to oxidative stress development manifested in age-related neurodegenerative diseases (NDD) and neurological disorders provoked by acute stress. Different forms of stress, the mostly studied being heat shock response, rely on functioning of heat shock proteins of the Hsp70 superfamily. Since kynurenines are called "kids of stress," we performed computational estimation of affinity of 3HOK and other kynurenines binding to predicted ATP site of Drosophila melanogaster Hsp cognate 71 protein (Dhsp71) using AutoDock Vina. The binding energy of 3HOK dimer is - 9.4 kcal/mol; its orientation within the active site is close to that of ATP. This might be a new mechanism of producing a competitive inhibitor of Hsp70 chaperones that decreases organism ability to adapt to heat shock. We also showed that the Drosophila cardinal (cd1) mutant with 3HOK excess, serving as a model for Huntington's disease (HD), manifests severe defects of short-term memory after heat shock applied either in adults or at the prepupal stage.


Assuntos
Proteínas de Drosophila , Cinurenina , Animais , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Resposta ao Choque Térmico , Cinurenina/análogos & derivados , Cinurenina/metabolismo , Ligantes
6.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445413

RESUMO

Chromatin 3D structure plays a crucial role in regulation of gene activity. Previous studies have envisioned spatial contact formations between chromatin domains with different epigenetic properties, protein compositions and transcription activity. This leaves specific DNA sequences that affect chromosome interactions. The Drosophila melanogaster polytene chromosomes are involved in non-allelic ectopic pairing. The mutant strain agnts3, a Drosophila model for Williams-Beuren syndrome, has an increased frequency of ectopic contacts (FEC) compared to the wild-type strain Canton-S (CS). Ectopic pairing can be mediated by some specific DNA sequences. In this study, using our Homology Segment Analysis software, we estimated the correlation between FEC and frequency of short matching DNA fragments (FMF) for all sections of the X chromosome of Drosophila CS and agnts3 strains. With fragment lengths of 50 nucleotides (nt), CS showed a specific FEC-FMF correlation for 20% of the sections involved in ectopic contacts. The correlation was unspecific in agnts3, which may indicate the alternative epigenetic mechanisms affecting FEC in the mutant strain. Most of the fragments that specifically contributed to FMF were related to 1.688 or 372-bp middle repeats. Thus, middle repetitive DNA may serve as an organizer of ectopic pairing.


Assuntos
Cromatina/química , DNA Satélite/genética , Drosophila melanogaster/genética , Síndrome de Williams/genética , Cromossomo X/genética , Animais , Pareamento de Bases , Cromatina/genética , Biologia Computacional/métodos , Modelos Animais de Doenças , Humanos , Cromossomos Politênicos/genética , Software
7.
Front Physiol ; 11: 971, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848886

RESUMO

Dysfunctions of kynurenine pathway of tryptophan metabolism (KPTM) are associated with multiple neuropathologies in vertebrates and invertebrates. Drosophila mutants with altered content of kynurenines are model objects for studying the molecular processes of neurodegeneration and senile dementia. The mutant cardinal (cd1 ) with accumulation of the redox stress inductor 3-hydroxykynurenine (3-HOK) shows age-dependent impairments of the courtship song and middle-term memory. The molecular mechanisms for 3-HOK accumulation in cd1 are still unknown. Here, we have studied age-dependent differences in spontaneous locomotor activity (SLA) for the wild type strain Canton-S (CS), cd1 , and cinnabar (cn1 ) with an excess of neuroprotective kynurenic acid (KYNA). We have also estimated the level and distribution of protein-bound 3-HOK (PB-3-HOK) in Drosophila brains (Br) and head tissues. The middle-age cd1 show the higher running speed and lower run frequency compared to CS, for cn1 the situation is the opposite. There is a decrease in the index of activity for 40-day-old cd1 that seems to be an effect of the oxidative stress development. Surprisingly, PB-3-HOK level in Drosophila heads, brains, and head capsules (HC) is several times lower for cd1 compared to CS. This complements the traditional hypothesis that cd1 phenotype results from a mutation in phenoxazinone synthase (PHS) gene governing the brown eye pigment xanthommatin synthesis. In addition to 3-HOK dimerization, cd1 mutation affects protein modification by 3-HOK. The accumulation of free 3-HOK in cd1 may result from the impairment of 3-HOK conjugation with some proteins of the brain and head tissues.

8.
PLoS Comput Biol ; 14(12): e1006672, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30532237

RESUMO

Kynurenines, the products of tryptophan oxidative degradation, are involved in multiple neuropathologies, such as Huntington's chorea, Parkinson's disease, senile dementia, etc. The major cause for hydroxykynurenines's neurotoxicity is the oxidative stress induced by the reactive oxygen species (ROS), the by-products of L-3-hydroxykynurenine (L-3HOK) and 3-hydroxyanthranilic acid (3HAA) oxidative self-dimerization. 2-aminophenol (2AP), a structural precursor of L-3HOK and 3HAA, undergoes the oxidative conjugation to form 2-aminophenoxazinone. There are several modes of 2AP dimerization, including both enzymatic and non-enzymatic stages. In this study, the free energies for 2AP, L-3HOK and 3HAA dimerization stages have been calculated at B3LYP/6-311G(d,p)//6-311+(O)+G(d) level, both in the gas phase and in heptane or water solution. For the intermediates, ionization potentials and electron affinities were calculated, as well as free energy and kinetics of molecular oxygen interaction with several non-enzymatically formed dimers. H-atom donating power of the intermediates increases upon the progress of the oxidation, making possible generation of hydroperoxyl radical or hydrogen peroxide from O2 at the last stages. Among the dimerization intermediates, 2-aminophenoxazinole derivatives have the lowest ionization potential and can reduce O2 to superoxide anion. The rate for O-H homolytic bond dissociation is significantly higher than that for C-H bond in non-enzymatic quinoneimine conjugate. However, the last reaction passes irreversibly, reducing O2 to hydroperoxyl radical. The inorganic ferrous iron and the heme group of Drosophila phenoxazinone synthase significantly reduce the energy cost of 2AP H-atom abstraction by O2. We have also shown experimentally that total antioxidant capacity decreases in Drosophila mutant cardinal with L-3HOK excess relative to the wild type Canton-S, and lipid peroxidation decreases in aged cardinal. Taken together, our data supports the conception of hydroxykynurenines' dual role in neurotoxicity: serving as antioxidants themselves, blocking lipid peroxidation by H-atom donation, they also can easily generate ROS upon dimerization, leading to the oxidative stress development.


Assuntos
Cinurenina/química , Cinurenina/metabolismo , Modelos Biológicos , Aminofenóis/química , Aminofenóis/metabolismo , Animais , Antioxidantes/metabolismo , Biologia Computacional , Dimerização , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Humanos , Cinurenina/toxicidade , Redes e Vias Metabólicas , Modelos Moleculares , Conformação Molecular , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Oxirredução , Estresse Oxidativo , Oxirredutases/química , Oxirredutases/genética , Oxirredutases/metabolismo , Oxigênio/química , Oxigênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Termodinâmica , Triptofano/metabolismo
9.
Front Genet ; 8: 123, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28979292

RESUMO

Genomic disorders, the syndromes with multiple manifestations, may occur sporadically due to unequal recombination in chromosomal regions with specific architecture. Therefore, each patient may carry an individual structural variant of DNA sequence (SV) with small insertions and deletions (INDELs) sometimes less than 10 bp. The transposable elements of the Tc1/mariner superfamily are often associated with hotspots for homologous recombination involved in human genetic disorders, such as Williams Beuren Syndromes (WBS) with LIM-kinase 1-dependent cognitive defects. The Drosophila melanogaster mutant agnts3 has unusual architecture of the agnostic locus harboring LIMK1: it is a hotspot of chromosome breaks, ectopic contacts, underreplication, and recombination. Here, we present the analysis of LIMK1-containing locus sequencing data in agnts3 and three D. melanogaster wild-type strains-Canton-S, Berlin, and Oregon-R. We found multiple strain-specific SVs, namely, single base changes and small INDEls. The specific feature of agnts3 is 28 bp A/T-rich insertion in intron 1 of LIMK1 and the insertion of mobile S-element from Tc1/mariner superfamily residing ~460 bp downstream LIMK1 3'UTR. Neither of SVs leads to amino acid substitutions in agnts3 LIMK1. However, they apparently affect the nucleosome distribution, non-canonical DNA structure formation and transcriptional factors binding. Interestingly, the overall expression of miRNAs including the biomarkers for human neurological diseases, is drastically reduced in agnts3 relative to the wild-type strains. Thus, LIMK1 DNA structure per se, as well as the pronounced changes in total miRNAs profile, probably lead to LIMK1 dysregulation and complex behavioral dysfunctions observed in agnts3 making this mutant a simple plausible Drosophila model for WBS.

10.
PLoS Comput Biol ; 12(11): e1005213, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27861556

RESUMO

Kynurenines, the main products of tryptophan catabolism, possess both prooxidant and anioxidant effects. Having multiple neuroactive properties, kynurenines are implicated in the development of neurological and cognitive disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. Autoxidation of 3-hydroxykynurenine (3HOK) and its derivatives, 3-hydroxyanthranilic acid (3HAA) and xanthommatin (XAN), leads to the hyperproduction of reactive oxygen species (ROS) which damage cell structures. At the same time, 3HOK and 3HAA have been shown to be powerful ROS scavengers. Their ability to quench free radicals is believed to result from the presence of the aromatic hydroxyl group which is able to easily abstract an electron and H-atom. In this study, the redox properties for kynurenines and several natural and synthetic antioxidants have been calculated at different levels of density functional theory in the gas phase and water solution. Hydroxyl bond dissociation enthalpy (BDE) and ionization potential (IP) for 3HOK and 3HAA appear to be lower than for xanthurenic acid (XAA), several phenolic antioxidants, and ascorbic acid. BDE and IP for the compounds with aromatic hydroxyl group are lower than for their precursors without hydroxyl group. The reaction rate for H donation to *O-atom of phenoxyl radical (Ph-O*) and methyl peroxy radical (Met-OO*) decreases in the following rankings: 3HOK ~ 3HAA > XAAOXO > XAAENOL. The enthalpy absolute value for Met-OO* addition to the aromatic ring of the antioxidant radical increases in the following rankings: 3HAA* < 3HOK* < XAAOXO* < XAAENOL*. Thus, the high free radical scavenging activity of 3HAA and 3HOK can be explained by the easiness of H-atom abstraction and transfer to O-atom of the free radical, rather than by Met-OO* addition to the kynurenine radical.


Assuntos
Antioxidantes/química , Cinurenina/química , Modelos Químicos , Modelos Moleculares , Oxigênio/química , Espécies Reativas de Oxigênio/química , Simulação por Computador , Ligação de Hidrogênio , Radical Hidroxila/química , Oxirredução
11.
J Bioinform Comput Biol ; 12(2): 1441005, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24712532

RESUMO

Using the combination of molecular dynamics (MD) simulations and geometric clustering we analyzed the role of arginine at 209 position in the transition of protein kinase A Iα (PKA Iα) regulatory subunit A-domain from H- to B-conformation and stabilization of the latter. The mechanism underlying the role of the residue at position 209 in the realization of B-conformation includes: (1) possibility to bind the ligand tightly (if transition happens in the presence of cAMP), (2) capability to hold ß2ß3-loop in the correct conformation, (3) tendency of residue at 209 position to stabilize B-conformation in the absence and in presence of the ligand. In terms of the effect produced on transition of A-domain from H- to B-conformation in the presence of cAMP, mutational substitutions for R209 can be arranged in the following order: Glu(Gly)>Lys>Ile. In the absence of cAMP the order is different Lys>Gly>Glu>Ile. Thus, our results allow us to presume that the role of arginine at 209 position can be important though not crucial.


Assuntos
Arginina/química , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/química , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/ultraestrutura , Proteínas Quinases Dependentes de AMP Cíclico/química , Proteínas Quinases Dependentes de AMP Cíclico/ultraestrutura , Modelos Químicos , Modelos Moleculares , Sítios de Ligação , Simulação por Computador , Ligação Proteica , Conformação Proteica , Estrutura Terciária de Proteína , Subunidades Proteicas
12.
PLoS One ; 9(4): e94975, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24736732

RESUMO

Aryl hydrocarbon receptor is essential for biological responses to endogenous and exogenous toxins in mammals. Its Drosophila homolog spineless plays an important role in fly morphogenesis. We have previously shown that during morphogenesis spineless genetically interacts with CG5017 gene, which encodes a nucleosome assembly factor and may affect cognitive function of the fly. We now demonstrate synergistic interactions of spineless and CG5017 in pathways controlling oxidative stress response and long-term memory formation in Drosophila melanogaster. Oxidative stress was induced by low doses of X-ray irradiation of flies carrying hypomorphic mutation of spineless, mutation of CG5017, and their combination. To determine the sensitivity of these mutants to pharmacological modifiers of the irradiation effect, we irradiated flies growing on standard medium supplemented by radiosensitizer furazidin and radioprotector serotonin. The effects of irradiation were investigated by analyzing leg and antenna morphological structures and by using real-time PCR to measure mRNA expression levels for spineless, Cyp6g1 and Gst-theta genes. We also examined long-term memory in these mutants using conditioned courtship suppression paradigm. Our results show that the interaction of spineless and CG5017 is important for regulation of morphogenesis, long-term memory formation, and detoxification during oxidative stress. Since spineless and CG5017 are evolutionary conserved, these results must be considered when evaluating the risk of combining similar mutations in other organisms, including humans.


Assuntos
Drosophila/genética , Drosophila/metabolismo , Memória , Morfogênese/genética , Mutação , Proteínas Nucleares/genética , Receptores de Hidrocarboneto Arílico/genética , Animais , Drosophila/embriologia , Drosophila/efeitos da radiação , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Epistasia Genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos da radiação , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Inativação Metabólica/genética , Aprendizagem , Masculino , Nucleossomos , Fenótipo , Receptores de Hidrocarboneto Arílico/metabolismo , Serotonina/farmacologia , Raios X
13.
J Mol Model ; 18(5): 1755-66, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21833825

RESUMO

Stacking interaction is known to play an important role in protein folding, enzyme-substrate and ligand-receptor complex formation. It has been shown to make a contribution into the aromatic antagonists binding with glutamate ionotropic receptors (iGluRs), in particular, the complex of NMDA receptor NR1 subunit with the kynurenic acid (KYNA) derivatives. The specificity of KYNA binding to the glutamate receptors subtypes might partially result from the differences in stacking interaction. We have calculated the optimal geometry and binding energy of KYNA dimers with the four types of aromatic amino acid residues in Rattus and Drosophila ionotropic iGluR subunits. All ab initio quantum chemical calculations were performed taking into account electron correlations at MP2 and MP4 perturbation theory levels. We have also investigated the potential energy surfaces (PES) of stacking and hydrogen bonds (HBs) within the receptor binding site and calculated the free energy of the ligand-receptor complex formation. The energy of stacking interaction depends both on the size of aromatic moieties and the electrostatic effects. The distribution of charges was shown to determine the geometry of polar aromatic ring dimers. Presumably, stacking interaction is important at the first stage of ligand binding when HBs are weak. The freedom of ligand movements and rotation within receptor site provides the precise tuning of the HBs pattern, while the incorrect stacking binding prohibits the ligand-receptor complex formation.


Assuntos
Proteínas de Drosophila/química , Ácido Cinurênico/química , Subunidades Proteicas/química , Receptores Ionotrópicos de Glutamato/química , Animais , Sítios de Ligação , Drosophila melanogaster , Ligação de Hidrogênio , Ligantes , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Teoria Quântica , Ratos , Eletricidade Estática , Termodinâmica
14.
Adv Exp Med Biol ; 527: 713-22, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-15206794

RESUMO

A search for Drosophila mutants with phenotypes similar to human diseases might help to unravel evolutionary conserved genes implicated in polygenic human disorders. Among these are neurodegenerative diseases, characterized by a late onset disturbance of memory, structural brain impairments and altered content of the intermediates of the kynurenine pathway. The ratio between kynurenate (KYNA) and 3-hydroxykynurenine (3-HOK) in the brain is a critical determinant of neuronal viability. Therefore, the Drosophila mutants cinnabar (KYNA excess) and cardinal (3-HOK excess) allow an evaluation of the specific roles of these metabolites which present in physiologic concentrations and mimic systemic administration. Previously we have demonstrated that the mutant cardinal can serve as a model for dementia and can help to unravel the earliest manifestations of brain dysfunction. Here we show that a state of the brain control of locomotor coordination characterized by the parameters of sound production in males results from the neuroprotective and neurotoxic effects of KYNA and 3-HOK accumulated in young and aged Drosophila mutants. The high instability of 1) cycle form and number in pulses; 2) of pulse amplitude and 3) rhythm in the courtship song of aged cardinal males are similar to the alterations in mutants with defective central complex of the brain. The cardinal mutants demonstrate apoptosis in the brain after stress treatment. This might reflect the misbalance in the content of excitatory amino acids' and the glycine site agonists revealed by HPLC-determination. The mutant cinnabar proved to be normal in respect of the parameters studied.


Assuntos
Envelhecimento/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Cinurenina/metabolismo , Mutação , Animais , Apoptose , Encéfalo/metabolismo , Encéfalo/patologia , Masculino , Modelos Biológicos , Comportamento Sexual Animal/fisiologia , Vocalização Animal/fisiologia
15.
BMC Neurosci ; 3: 9, 2002 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-12149133

RESUMO

BACKGROUND: Starting from Benzer's initiative, the approach of forward genetics has been widely used to isolate mutations affecting learning and memory. For this aim, mainly the odor-shock conditioning was employed. We have isolated P insertional mutations affecting memory after courtship conditioning - another form of classical conditioning in Drosophila. Here we report the behavioral characteristics of one of these mutants, which we have called nemy (no extended memory). RESULTS: The courtship activity of Drosophila males is reduced when a male has a previous experience of courting a fertilized female. In the wild-type strain C-S (K), this conditioned courtship inhibition lasts for 1-3 h in the test with a virgin female, and at least for 8 h in the test with a subsequent fertilized female. The mutant males nemyP153 display distinct memory deficiency in both tests already 0.5 h after training. The mutant males show an increased level of locomotor activity unrelated to courtship, and spend more time in such an element of courtship as pursuit. This, however, seems to be a pleiotropic effect of the mutation, independent from its influence on the courtship conditioning. The mutation reduces also memory performance after the odor-shock classical conditioning. At the same time, the sensory and motor functions involved in this type of learning seem to be normal. CONCLUSIONS: Insertion of P-lacW vector into 49B region of the second chromosome (mutation nemyP153) causes an increased level of locomotor activity, memory deficiency after the courtship conditioning and subnormal acquisition after the odor-shock conditioning.


Assuntos
Comportamento Animal/fisiologia , Drosophila melanogaster/fisiologia , Memória/fisiologia , Mutação , Animais , Condicionamento Clássico , Corte , Eletrochoque , Feminino , Aprendizagem/fisiologia , Masculino , Atividade Motora/fisiologia , Retenção Psicológica/fisiologia , Comportamento Sexual Animal/fisiologia , Olfato/fisiologia , Estimulação Química
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