L. Gerosa
THE ACTIVITY DEPENDENT CLEAVAGE AND NUCLEAR FUNCTION OF FEMALE LIMITED EPILEPSY PROTEIN PCDH19 [Tesi di dottorato]
Università degli Studi di Milano, 2016-01-11

PCDH19-female limited epilepsy is characterized by seizures onset in infancy or early childhood, cognitive impairment and behavioral disturbances. PCDH19 gene, located at the X-chromosome, is the causative gene and till now have been identified more than 100 different pathogenic point mutations. Peculiar features of PCDH19-FLE are the unusual inheritance pattern and the existence of various phenotypic degrees, even between patients carrying the same mutation. There are several hypotheses that try to explain the pathogenic mechanism. However a clear and precise explanation is still lacking. Moreover, little is known about the expression and functions of PCDH19 protein encoded by the FLE causative gene. Thus, the principal aim of our work is to go deeper into PCDH19 physiological functions in order to understand which kind of pathways could be impaired in patients and highlight crucial points altered in pathological conditions that could represent new therapeutic targets. The first part of our work aimed to define PCDH19 expression in rat brain and in neuronal cells. In particular we investigated PCDH19 expression level in different adult rat brain regions and we analyzed the subcellular localization of PCDH19 in cultured hippocampal neurons. In the second part of the work we investigated PCDH19 neuronal functions, in particular we examined a new molecular mechanism by which PCDH19 could link external stimuli with intracellular compartment focusing more on its putative intracellular functions. Then, we investigated the effect of PCDH19 loss in cultured hippocampal neurons. We used a shRNA strategy that induces loss of expression of PCDH19 resembling PCDH19-FLE condition and we analyzed which targets are impaired by PCDH19 knockdown. Once we obtained putative targets, we went deeper into the molecular and functional mechanism that links PCDH19 protein to these targets in order to clarify the pathways in which PCDH19 plays an important role and that could be impaired by the loss of PCDH19 expression. The results would facilitate the identification of new therapeutic targets.

diritti: info:eu-repo/semantics/openAccess
In relazione con info:eu-repo/semantics/altIdentifier/hdl/2434/347502
DILUCA, MONICA MARIA GRAZIA
coordinatore: A. Corsini ; relatore: M. Diluca ; correlatore: M. Passafaro
CORSINI, ALBERTO
Settore BIO/14 - - Farmacologia


Tesi di dottorato. | Lingua: Inglese. | Paese: | BID: TD18002274