The 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 (Catsup26 ) with elevated DA levels, and pale (ple2 ), Punch (PuZ22 ) 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 ple2 mutants with depleted DA levels. This phenotype was abolished in the ple2 rescue flies. Interestingly, females also demonstrated marked age-related decline in circadian locomotor activity compared with males. Old Catsup26 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, ple2 and PuZ22 mutant males. In Catsup26 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.

• Klíčová slova
• 4-hydroxynonenal, aging, circadian rhythms, lifespan, protein carbonyl,
• MeSH
• cirkadiánní hodiny MeSH
• dopamin genetika   metabolismus   MeSH
• Drosophila melanogaster MeSH
• genotyp MeSH
• homeostáza * MeSH
• lokomoce MeSH
• peroxidace lipidů MeSH
• proteiny Drosophily genetika   metabolismus   MeSH
• sexuální faktory MeSH
• stárnutí genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• catsup protein, Drosophila MeSH Prohlížeč
• dopamin MeSH
• proteiny Drosophily MeSH

The 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(Δ14)), which is required for packaging of DA as vesicles inside DA neurons. Median lifespans of ple(2), Pu(Z22) and VMAT(Δ14) 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 μM) or paraquat (10mM) compared to ple(2), Pu(Z22) or VMAT(Δ14) and controls. These flies also exhibited significantly higher negative geotaxis activity compared to ple(2), Pu(Z22), VMAT(Δ14) and controls. All mutant flies demonstrated rhythmic circadian locomotor activity in general, albeit Catsup(26) and VMAT(Δ14) 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(Δ14) 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.

• Klíčová slova
• Catecholamine, Circadian, Dopamine, Drosophila, Glutathione-S-transferase, Oxidative stress,
• MeSH
• antioxidancia MeSH
• biologické markery metabolismus   MeSH
• cirkadiánní rytmus fyziologie   MeSH
• dopamin biosyntéza   genetika   metabolismus   MeSH
• Drosophila melanogaster genetika   fyziologie   MeSH
• genetické markery MeSH
• geneticky modifikovaná zvířata MeSH
• glutathiontransferasa genetika   metabolismus   MeSH
• hmyzí geny MeSH
• mutace MeSH
• náhodné rozdělení MeSH
• oxidační stres genetika   fyziologie   MeSH
• pohybová aktivita genetika   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• antioxidancia MeSH
• biologické markery MeSH
• dopamin MeSH
• genetické markery MeSH
• glutathiontransferasa MeSH