Unit:
Specialty Molecular Biomedicine Mechanisms of Disease, Molecular and Cellular Therapies, and BioinnovationLibrary of the School of Health Sciences
Supervisors info:
Ευθύμιος Σκουλάκης, Ερευνητής Α΄, Κέντρο Ιατροβιολογικών Ερευνών «Αλέξανδρος Φλέμινγκ», Επιβλέπων
Αντώνιος Σταματάκης, Αναπληρωτής Καθηγητής, Τμήμα Νοσηλευτικής, ΕΚΠΑ
Χρήστος Κόνσουλας, Αναπληρωτής Καθηγητής, Τμήμα Ιατρικής, ΕΚΠΑ
Original Title:
Neuron specific functions of neurofibromin in learning and memory
Translated title:
Neuron specific functions of neurofibromin in learning and memory
Summary:
Neurofibromatosis Type1 (NF1) is a commonly inherited genetic disorder. It results from loss-of-function mutations in the Nf1 gene encoding Neurofibromin (Nf1), a ubiquitously expressed protein, which, among others, functions as a negative regulator of RAS activity and an activator of adenylyl cyclase (AC). The main phenotype of Neurofibromatosis 1 (NF1) is the development of tumors involving the nervous system. However, 50-80% of children with NF1 also manifest diverse cognitive impairments. Despite this percentage, the molecular mechanisms and neuronal circuits underlying these impairments remain unclear, resulting to lack of pharmaceutical treatment.
Previous work of the Skoulakis Lab, working with Drosophila melanogaster, as a model organism has shown that loss of the highly conserved Drosophila dNf1 ortholog results in deficits in associative learning and memory, thus resembling human NF1 cognitive symptoms. As far as learning is concerned, the expression of Nf1 was shown to be essential in specific GABAergic neurons that seem to project to the mushroom bodies (MBs), the main center of olfactory learning and memory in insects. Moreover, experimental data prove that learning deficits of Nf1 deficient flies can be reversed upon inhibition of the Alk receptor tyrosine kinase in the same GABAergic neurons. Alk has been shown to act as a negative regulator of olfactory learning and memory in neurons outside and inside MBs, respectively. We speculate that the complexity and variety of NF1’s cognitive symptoms reflect a functional disruption of Nf1 that affects distinct biochemical pathways and mechanisms in different neurons related to learning and memory. Thus it is crucial that the respective neuronal circuits to which both the expression and the interaction -if there is one- of Nf1 and Alk are essential for normal memory are identified. Interestingly, while independent work suggests a role for Nf1 inside the MBs for normal memory, the results of this thesis provide evidence that it is required in neurons outside the MBs, as in learning.
Main subject category:
Health Sciences
Keywords:
Neurofibromin, NF1, Learning, Memory, Cognitive functions
