Μοριακά μονοπάτια ρυθμιζόμενα από την πρωτεΐνη Drk στην μάθηση και την ανεξάρτητη της πρωτεϊνοσύνθεσης μνήμη στο Drosophila melanogaster
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Μανώλης, Αθανασίος
Manolis, Athanasios
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Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής
University of Ioannina. School of Health Sciences. Department of Medicine.
University of Ioannina. School of Health Sciences. Department of Medicine.
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Η κατανόηση των μοριακών μηχανισμών που διέπουν τη μνήμη είναι αναγκαία για την ανάπτυξη μεθόδων προς αντιμετώπιση διαταραχών της μνήμης, συμπεριλαμβανομένων των νευροεκφυλιστικών νοσημάτων και των γνωσιακών παθήσεων που σχετίζονται με την γήρανση. Η μάθηση και η μνήμη μελετώνται σε θηλαστικά και απλούστερους οργανισμούς μοντέλα, όπως η Drosophila melanogaster.
Ενδιαφέρον προκαλεί το γεγονός ότι οι μύγες μπορούν να σχηματίσουν έναν τύπο μνήμης που, αντίθετα από την ευρέως μελετημένη μακροπρόθεσμη μνήμη, είναι ανεξάρτητος από τη σύνθεση νέων πρωτεϊνών (Protein Synthesis Independent Memory-PSIM). Παρόλο που η PSIM έχει προσδιοριστεί μόνο στη Drosophila, είναι απίθανο να μην έχει διατηρηθεί μέσω της εξέλιξης. Πράγματι, ορισμένα χαρακτηριστικά της PSIM έχουν αναγνωριστεί σε άλλα ασπόνδυλα και σπονδυλωτά, όπως ο άνθρωπος. Επειδή οι μηχανισμοί που διέπουν την PSIM είναι σε μεγάλο βαθμό άγνωστοι, χρησιμοποιήθηκε η μέθοδος της εντεταμένης εκπαίδευσης (Massed Conditioning-MC), που οδηγεί αποκλειστικά στο σχηματισμό PSIM, για να αποκαλυφθούν μοριακά στοιχεία αυτής της νέας μνήμης στη Drosophila. Προηγούμενες μελέτες του εργαστηρίου έχουν δείξει ότι η πρωτεΐνη Drk, η οποία δρα κάτω από υποδοχείς κινάσης-τυροσίνης, είναι απαραίτητη στα Μισχοειδή Σωμάτια (Mushroom Bodies-MBs), το "κέντρο" της μάθησης και της μνήμης στη μύγα, για την κανονική μνήμη που προκαλείται από την MC. Από πρωτεομική ανάλυση εντός των ενήλικων MBs, εντοπίστηκε ένας αριθμός πρωτεϊνών που πιθανά αλληλεπιδρούν με την Drk, συμπεριλαμβανομένων νέων μορίων που ενέχονται στην PSIM και ίσως
συμμετέχουν στα ίδια σηματοδοτικά μονοπάτια με την Drk. Η παρούσα μελέτη παρουσιάζει τη λειτουργική επαλήθευση αυτών των πρωτεϊνών που αλληλεπιδρούν με την Drk, η οποία υποστηρίζει τον ρόλο ορισμένων από αυτές στην μνήμη που προκαλείται από την MC. Η περαιτέρω μελέτη της λειτουργίας και της σηματοδότησής τους θα συμβάλει, ελπίζουμε, στην κατανόηση των μηχανισμών που βρίσκονται στη βάση των μνημών που είναι ανεξάρτητες της σύνθεσης πρωτεϊνών, όχι μόνο στη Drosophila, αλλά και στα θηλαστικά.
Understanding the molecular mechanisms that govern memory is necessary to develop methods to combat memory disorders including dementias and age-dependent cognitive impairments. Learning and memory are being studied in mammalian and simpler model organisms, as Drosophila melanogaster. Interestingly, flies are able to form a memory type which unlike the well-studied Long-Term Memory is independent of novel protein synthesis (PSIM). Although PSIM has been identified only in Drosophila, it is unlikely that it has not been conserved through evolution. In fact, PSIM- characteristics have been identified in other invertebrates and vertebrates, including humans. Since the mechanisms that govern PSIM are largely unknown, the massed conditioning (MC) training method, which solely yields PSIM, was used to reveal molecular components of this novel memory in Drosophila. Previous studies in the lab have revealed that the adaptor protein Drk, which acts downstream of tyrosine kinase receptors, is essential in the Mushroom Bodies (MBs), -the center of learning and memory in flies- for normal MC-elicited memory. Proteomic analysis within the adult MBs helped identification of probable Drk-interacting proteins, including novel molecules that are engaged in PSIM and might participate in the same signaling pathway as Drk . The present study presents a functional validation of these Drk interacting proteins, which supports roles for a number of them in MC-elicited memory. Further study of their function and signaling will hopefully aid our understanding of the mechanisms that underlie protein synthesis-independent memories not only in Drosophila, but also in mammals.
Understanding the molecular mechanisms that govern memory is necessary to develop methods to combat memory disorders including dementias and age-dependent cognitive impairments. Learning and memory are being studied in mammalian and simpler model organisms, as Drosophila melanogaster. Interestingly, flies are able to form a memory type which unlike the well-studied Long-Term Memory is independent of novel protein synthesis (PSIM). Although PSIM has been identified only in Drosophila, it is unlikely that it has not been conserved through evolution. In fact, PSIM- characteristics have been identified in other invertebrates and vertebrates, including humans. Since the mechanisms that govern PSIM are largely unknown, the massed conditioning (MC) training method, which solely yields PSIM, was used to reveal molecular components of this novel memory in Drosophila. Previous studies in the lab have revealed that the adaptor protein Drk, which acts downstream of tyrosine kinase receptors, is essential in the Mushroom Bodies (MBs), -the center of learning and memory in flies- for normal MC-elicited memory. Proteomic analysis within the adult MBs helped identification of probable Drk-interacting proteins, including novel molecules that are engaged in PSIM and might participate in the same signaling pathway as Drk . The present study presents a functional validation of these Drk interacting proteins, which supports roles for a number of them in MC-elicited memory. Further study of their function and signaling will hopefully aid our understanding of the mechanisms that underlie protein synthesis-independent memories not only in Drosophila, but also in mammals.
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Μνήμη, Memory, Δροσόφιλα, Drosophila melanogaster, Ανεξάρτητη της πρωτεϊνοσύνθεσης μνήμη, Protein-synthesis independent memory, Οσφρητική εξαρτημενή μάθηση, Olfactory conditioning
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en
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Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής
University of Ioannina. School of Health Sciences. Department of Medicine.
University of Ioannina. School of Health Sciences. Department of Medicine.
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Σκουλάκης, Ευθύμιος
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Σκουλάκης, Ευθύμιος
Skoulakis, Efthimios M.C.
Μιχαηλίδης, Θεολόγος
Michaelidis, Theologos
Λαμπρακάκης, Χαράλαμπος
Labrakakis, Charalampos
Skoulakis, Efthimios M.C.
Μιχαηλίδης, Θεολόγος
Michaelidis, Theologos
Λαμπρακάκης, Χαράλαμπος
Labrakakis, Charalampos
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Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας
University of Ioannina. School of Health Sciences
University of Ioannina. School of Health Sciences
Table of contents
A. ΠΕΡΙΛΗΨΗ
B. ABSTRACT
C. INTRODUCTION
1. Learning and memory
1.1. Definition of memory
1.2. Types of memory
1.3. How do we study behavior?
1.4. Associative memory and the Pavlovian assay
2. Drosophila melanogaster
2.1. Drosophila in biomedical research
2.2. Life cycle
2.3. Genetic tools and molecular techniques
3. Mushroom Bodies-Center of olfactory learning and memory in
Drosophila melanogaster
3.1. Anatomy
3.2 Function and role in learning and memory
4. Learning and memory in Drosophila
4.1. Memory phases in Drosophila
4.2. Anesthesia Resistant Memory (ARM)
4.3. ARM vs LTM
4.4. Distinction between ARM and MC-Elicited Memory
5. Molecular pathways involved in learning and memory
5.1. RAS/RAF/MAPK pathway
6. The protein Drk/GRB2
6.1. Role in learning and memory
6.2. Drk Reduction Selectively Affects PSIM
D. AIM-IMPORTANCE OF PRESENT STUDY
E. EXPERIMENTAL PROCEDURES
1. Drosophila cultures and strains
2. Behavioral assays
3. Western blotting
4. Phalloidin Staining and Confocal Microscopy
5. Statistical analysisTable of contents
F. RESULTS
A. Previous data from Skoulakis lab (unpublished data)
B. Data from experiments conducted for this thesis
1. Behavioral part
2. Molecular part
G. DISCUSSION
H. APPENDIX
I. REFERENCES
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51 σ.
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Except where otherwised noted, this item's license is described as Attribution-NonCommercial-NoDerivs 3.0 United States