Degradation_ID · The role of protein degradation in FBXO11-related intellectual disability
„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“
- Период
- 2019-07-01 → 2021-07-31
- Финансиране от ЕС
- 174 806 €
- Участници
- 2
- Схема
- MSCA-IF-EF-RI
Линиите свързват координатора с партньорите.
Накратко на български
Ролята на протеина FBXO11 при разграждането на ненужни молекули в нервните клетки се анализира чрез модели с плодови мухи. Разбирането на тези процеси помага за откриването на начини за подобряване на състоянието при определени нарушения в развитието на мозъка.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
The role of protein degradation in FBXO11-related intellectual disability
Neurodevelopmental disorders (NDDs) affect 1-3% of the population and therefore represent an important health and socioeconomic problem worldwide. Genetic causes of NDDs are very heterogenous with currently variants in more than 1500 genes identified. Understanding pathomechanisms of NDDs is greatly lacking behind novel disease gene associations, thus hindering development of causative therapies. There, understanding pathomechanisms is crucial for future explorations of therapeutic development. Many disease genes can be clustered in functionally coherent modules. A promising idea is to identify functional and pathomechanistic commonalities in those modules to eventually tackle multiple genes by targeting a single central pathway, process, or molecule. One such emerging module is protein ubiquitination and protein degradation, in which only recently a growing number of genes/proteins was associated with NDDs. FBXO11 encodes an E3-ubiquitin ligase, and variants in this gene have recently been associated with a variable neurodevelopmental disorder. The first objective of this project was to characterize the molecular functions of FBXO11 in the nervous system and to investigate the role of altered degradation pathogenesis of NDDs in human neuronal cells. The second objective was to model Fbxo11 deficiency in the model organism Drosophila melanogaster to identify strategies for chemical intervention to alter phenotypes. In this project, I could show that deficiency of FBXO11 impairs programs for neuronal differentiation and dendrite formation, and that in the model organism Drosophila melanogaster some of the phenotypes resulting from Fbxo11 deficiency can be ameliorated by chemical intervention.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
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.
Оригинален текст от CORDIS (на английски).
Участници
Връзки
Данни: CORDIS, © Европейски съюз