Descrizione del progetto
Omeostasi proteica durante il neurosviluppo
I disturbi del neurosviluppo (DN) influiscono sullo sviluppo e sulle funzioni cerebrali e si manifestano con un’eterogeneità genetica e fenotipica. Recenti prove scientifiche evidenziano il ruolo dell’omeostasi proteica anomala in questi disturbi. Il progetto Degradation_ID, finanziato dall’UE, si propone di offrire approfondimenti sui componenti del meccanismo di omeostasi proteica. A tale scopo, i ricercatori concentreranno l’attenzione su FBXO11, nota per la sua capacità di modificare le proteine destinate alla degradazione. Le mutazioni di FBXO11 sono state collegate ai DN, perciò è necessaria una maggiore comprensione dei meccanismi di funzionamento di tale proteina nel neurosviluppo. Nel corso del progetto si utilizzerà Drosophila melanogaster per modellare la carenza di FBXO11 e analizzare vari attivatori del proteasoma come strategia per superare l’indebolimento della degradazione delle proteine.
Obiettivo
Neurodevelopmental disorders (NDDs) are genetically extremely heterogeneous with mutations in more than 1000 genes being causative. NDD-related genes and encoded proteins are involved in a wide range of various biological processes. Recently, several genes involved in protein degradation have been implicated in NDDs. This suggests that defects in protein homeostasis may be a recurring theme in neurodevelopment and cognition. We have recently identified de novo mutations in the nuclear E3-ubiquitin ligase complex component FBXO11 in 20 patients with a variable neurodevelopmental disorder. Loss-of function or haploinsufficiency of FBXO11 is the most likely mechanism for FBXO11-related NDDs. The pathomechanism of how FBXO11deficiency may lead to (neuro)-developmental defects has yet to be established. The objective of this project is to understand the role FBXO11 defects may play in the development of NDDs. In aim 1 I will focus on deciphering the molecular function of FBXO11 using two complementary approaches: identifying FBXO11 substrates using affinity-purification mass-spectrometry approaches and identifying pathways affected by FBXO11 dosage alterations using transcriptomic approaches. The identification of FBXO11 substrates and downstream pathways will lead to a better understanding of its role in neurodevelopment and in NDDs. In aim 2 I will characterize the role of Fbxo11 in neurodevelopment by modeling Fbxo11 deficiency in Drosophila melanogaster and investigate the potential to manipulate phenotypes by supplementation of fly food with proteasome activators. Collectively, this project will furthermore open a window to better understand the role alterations of protein degradation may play for NDDs in general.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF-EF-RI - RI – Reintegration panelCoordinatore
3012 Bern
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