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Transcriptomic and Proteomic Studies on Longevity Induced by Over-Expression of Hsp22 in Drosophila Melanogaster

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Transcriptomic and Proteomic Studies on Longevity Induced by Over-Expression of Hsp22 in Drosophila Melanogaster HYUN-JU KIM TRANSCRIPTOMIC AND PROTEOMIC STUDIES ON LONGEVITY INDUCED BY OVER-EXPRESSION OF HSP22 IN DROSOPHILA MELANOGASTER Thèse présentée à la Faculté des études supérieures de l’Université Laval dans le cadre du programme de doctorat en Biologie Cellulaire et Moléculaire pour l’obtention du grade de Philosophiae Doctor (Ph. D.) FACULTÉ DE MÉDECINE UNIVERSITÉ LAVAL QUÉBEC 2008 © Hyun-Ju Kim, 2008 i Résumé Le vieillissement est un processus complexe accompagné par une capacité diminuée des cellules à tolérer et répondre aux formes différentes de stress causant des dommages comme l'agrégation de protéine dans les différentes composantes de la cellule. Les chaperons sont des joueurs probablement importants dans le processus de vieillissement en prévenant la dénaturation et l'agrégation des protéines. Chez Drosophila melanogaster, une petite protéine de choc thermique, Hsp22, localisée dans la matrice mitochondriale montre une expression elevée pendant le vieillissement. Sa surexpression chez la mouche augmente la durée moyenne de vie ainsi que la résistance au stress. Bien que Hsp22 montre une activité de chaperon dans des essais in vitro, les mécanismes par lesquels Hsp22 permet d’accroitre la durée de vie in vivo sont toujours inconnus. Une analyse transcriptionelle de tout le génome par microarrays et une analyse comparative du protéome mitochondrial par MALDI-TOF a été entreprise pour dévoiler les différences d’expression entre les mouches surexprimant Hsp22 et les contrôles appropriés. La surexpression générale de Hsp22 en utilisant le système GAL4/UAS dans Drosophila résulte en une augmentation de ~ 30% dans la durée de vie moyenne. L'analyse du transcriptome suggère que Hsp22 joue un rôle dans la détermination de durée de vie en changeant le processus général de vieillissement normal. Effectivement, les mouches surexprimant Hsp22 affichent une surexpression de gènes dont l’expression baisse normalement durant le vieillissement. Les gènes sont impliqués dans la production d'énergie, la biosynthèse des protéines, le taux de renouvellement des protéines et le métabolisme lipidique. L'analyse du protéome mitochondrial soutient aussi un rôle de Hsp22 sur la détermination de la durée de vie en maintenant la fonction mitochondriale et en favorisant la protéolyse. Les présentes données suggèrent l'importance de la maintenance de l’homéostasie protéique durant le vieillissement et discutent des mécanismes potentiels d’extension de la longévitié chez les mouches surexprimant Hsp22. ii Abstract Aging is a complex process accompanied by a decreased capacity of cells to tolerate and respond to various forms of stresses leading to damages such as protein aggregation in various components of the cell. Chaperones are thus likely important players in the aging process by preventing protein denaturation and aggregation. In Drosophila melanogaster, a small heat shock protein Hsp22 localized in the mitochondrial matrix is preferentially up- regulated during aging. Its over-expression results in an extension of lifespan and an increased resistance to stress. Although Hsp22 has been shown to have a chaperone-like activity in vitro, the mechanisms by which it extends lifespan in vivo are still unknown. Genome-wide transcriptional analysis by microarray and comparative mitochondrial proteomic analysis by MALDI-TOF mass analysis have been performed to unveil differences in long-lived Hsp22 over-expressing flies and normal-lived control flies. Ubiquitous over-expression of Hsp22 using the GAL4/UAS system in Drosophila resulted in a ~ 30% increase in mean lifespan. The genomic analysis suggests that Hsp22 plays a role in lifespan determination by altering the regulation of the overall process of normal aging. Indeed, flies over-expressing Hsp22 display an up-regulation of genes normally down-regulated with age and involved in energy production, protein biosynthesis, protein turnover, and lipid metabolism. Mitochondrial proteomic analysis also supports a putative role of Hsp22 on lifespan determination by maintaining mitochondrial function and favoring proteolysis. The present data suggest the importance of the maintenance of protein homeostasis in aging and potential mechanisms of longevity in the Hsp22 over-expressing flies. iii Preface Although a large body of studies on the aging process has been performed for several decades, the mechanisms involved are complex and still highly debated. Many members of heat shock protein families (Hsps) have been implicated to influence the aging process in different organisms. The present study focusses on the mitochondrial chaperone Hsp22 in Drosophila melanogaster, and aims to unveil a detailed mechanism by which over- expression of Hsp22 prolongs longevity. General introductions on the aging process and the heat shock protein families are described in Chapter 1. In Chapter 2, the longevity observed in flies over-expressing Hsp22 and several physiological features are compared with control flies. To define the differences in genome transcription and in proteome of Hsp22 over-expressing flies, we performed mitochondrial proteomic/transcriptomic comparisons. Chapter 3 validates the methodology of mitochondrial isolation and assessment of the purifity of the mitochondrial fraction. Chapter 4 describes a proteomic analysis of mitochondria and electron transport chain activity. Chapter 5 presents the transcriptomic analysis. On the basis of overall data obtained in this study, a potential mechanism of longevity in long-lived flies over- expressing Hsp22 is discussed in Chapter 6. I would like to sincerely thank all the members of the jury for their effort to evaluate my Ph D. thesis. Since September 2003, Dr. Robert, M. Tanguay has been the best supervisor for my Ph.D study. I have been impressed and encouraged a lot by his silent instruction. It was like a beacon light on the ocean. He printed out newly updated papers on aging study, kindly handwrited my name on top of the papers and layed them on my desk before my arriving in early morning. In addition, attending MiMage and LINK-AGE joint Summer School on Models and Methods in Ageing Research (Les Diablerets, Switzerland) last autumn was a great experience. I would like to thank my supervisor a lot for his thoughtful consideration. iv I would also like to thank Dr. Geneviève Morrow for all of her help during my Ph.D study. She has helped me in numerous tasks like beginning Drosophila work, giving a private lesson by translating French-written slides of lecture as well as experimental discussion. I would like to thank all the persons who kindly gave me help and discussion for detailed experiments: Dr. Sébastien Michaud (CHUL), Dr. Timothy Westwood (Canadian Drosophila Microarray Centre), Dr. Robert Faure (CHUL), and Dr. André Schrattenholz (ProteoSys AG). Also, I would like to thank all professional persons who kindly gave technical support in proteomic analysis (Dr. Sylvie Bourassa (Proteomic center, CHUL), Dr. Karlfried Groebe (ProteoSys AG)), and in microarray analysis (Dr. Jianming Pei / Dr. Scott Neal / Mr. Kaiguo Mo, Canadian Drosophila Microarray Centre). I would like to thank all the members in laboratory for their friendship and kind attention: Diana, Marie, Åsa, Hoda, Iuliana and Marie-Claire. I would like to thank Johanne who is my Quebecoise mother, all of my loving family & friends, and Dr. Du-Hyun Kim & Dr. Hitoshi Iwahashi who were my previous directors. I would finally like to thank all research foundations which have supported this study: Canadian Institutes of Health Research, MiMage (Mitochondrial Mechanisms of Ageing) European Commission, CREFSIP (Centre de recherche sur la fonction, la structure et l'ingénierie des proteins), and la Fondation de l’Université Laval. v List of figures Fig. 1-1. Regulatory mechanisms of the prokaryotic heat shock response......................8 Fig. 1-2. Example of HSEs within human hsp70.1 promoter site.....................................9 Fig. 1-3. Schematic analysis for conserved domains of heat shock transcriptional factors among various organisms..............................................................................10 Fig. 1-4. Evolutionary relationships of HSF family .........................................................11 Fig. 1-5. Proposed mechanism of regulation of the heat shock response.......................13 Fig. 1-6. Schematic description of GroEL-GroES chaperonin system ..........................15 Fig. 1-7. Schematic representation of human and mouse Hsp27 protein ......................18 Fig. 1-8. In vitro chaperone-like activity of small heat shock proteins...........................23 Fig. 1-9. Major sites of ROS generation, complex specific inhibitors and scavenging enzymes in the mitochondrial respiratory chain .....................................................26 Fig. 1-10. Production of protein carbonyls.......................................................................29 Fig. 2-1. Gene map of EP(3)3247 line and schematic design for Hsp22 over-expression by GAL4/UAS system.................................................................................................41 Fig. 2-2. Schematic overview of protein carbonylation assay.........................................44 Fig. 2-3. Prolonged lifespan in Hsp22 over-expressing flies............................................46 Fig. 2-4. Protein profile and pattern of heat shock proteins expression during aging in Hsp22 over-expressing flies and Hsp22 normal-expressing flies............................48 Fig. 2-5.
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