Unit:
Faculty of MedicineLibrary of the School of Health Sciences
Dissertation committee:
Σανούδου Δέσποινα, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ, Επιβλέπουσα
Καπετανάκη Γιασεμή, Καθηγήτρια και Ερευνήτρια Α΄, ΙΙΒΕΑΑ
Πάντος Κωνσταντίνος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ηλιοδρομίτης Ευστάθιος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Παπαπετρόπουλος Ανδρέας, Καθηγητής, Τμήμα Φαρμακευτικής, ΕΚΠΑ
Μαυροειδής Μανώλης. Ερευνητής Γ΄, ΙΙΒΕΑΑ
Βασιλάτης Δημήτριος, Ερευνητής Γ΄, ΙΙΒΕΑΑ
Original Title:
Ο ρόλος της myospryn in vivo και η σημασία της αλληλεπίδρασής της με τη δεσμίνη
Translated title:
The role of myospryn in vivo and the significance of its association with desmin
Summary:
The TRIM-like protein myospryn is a desmin associated protein, initially identified as an associated partner to the BLOC-1 (Biogenesis of Lysosomes Related Organelles Complex 1) protein dysbindin, implicating its potential involvement in vesicle trafficking and organelle biogenesis and/or positioning. Myospryn is also an AKAP protein (A Kinase Anchoring Protein) raising the possibility that together with desmin and other cytoskeletal and signaling proteins, it could participate in the subcellular targeting of protein kinase A (PKA) activity in striated muscle. Considering the previous data, we sought to unveil the role of myospryn in heart and the biological significance of myospryn-desmin association. To address this we have used both in vivo and in vitro strategies. With in vitro approaches we have studied the importance of desmin-AKAP/myospryn interaction in the regulation of PKA pathway. We used neonatal cardiomyocytes and showed that desmin deficiency affects at least the beating rate, the recycling of the b2 adrenergic receptor and cyclic-AMP accumulation, suggesting a potential role of desmin and desmin-AKAP/myospryn association in proper β-AR/adenylate cyclase coupling and receptor desensitization that might contribute to heart failure development due to desmin deficiency. With in vivo approaches, we further elucidated the role of myospryn in heart and the biological significance of myospryn-desmin association. We genetically inactivated myospryn in mice via homologous recombination in embryonic stem cells (ESCs) with the efficiency of homologous recombination being only 0,9%. This is the first worldwide description of the generation of myospryn knockout mouse, which by itself demonstrated that, the absence of myospryn does not cause embryonic lethality in mice. The absence of myospryn causes dilated cardiomyopathy, characterized by wall thinning and dilation, abnormalities in heart chambers (by-atrial dilation), fibrosis and compromised cardiac function. Ultrastructural analyses revealed that the sarcomere organization is not obviously affected, with the myofibrils being well packaged and organized, however, intercalated disk (ID) integrity is impaired. The most important finding of the present study is the severe mitochondrial defects with abnormal internal mitochondrial vacuoles and extensive cristolysis, often accompanied by swollen sarcoplasmic reticulum (SR) and T-tubules, without excluding abnormal mitophagy. Overall, our data imply a potential link of myospryn together with desmin to SR-mitochondrial physical and functional cross-talk through ΜΑΜs (mitochondrial-associated ER membranes).
Main subject category:
Health Sciences
Keywords:
Cytoskeleton, Desmin, Myospryn, Mitochondria, Lysosomes, Trafficking
Number of references:
358
