NUP153 - Nup153 as target to improve neurogenesis and cognitive function in AD (DIT.AD010.040)

Thematic area

Engineering, ICT and technologies for energy and transportation

Project area

Structure responsible for the research project

Institute for system analysis and computer science "Antonio Ruberti" (IASI)

Project manager

CLAUDIA COLUSSI
Phone number: 0630154966
Email: Claudia.Colussi@cnr.it

Abstract

Increasing evidence indicates that impaired adult neurogenesis is an early event in AD that plays a crucial role in cognitive dysfunction associated with the pathology. Thus, the discovery of new factors able to regulate adult neurogenesis may be a powerful tool to promote repair and support the brain's regenerative capacity. Epigenetic mechanisms, modifying chromatin without changing the primary DNA sequences, are fundamental in controlling gene expression in several physiological processes including adult neurogenesis. Although a number of epigenetic alterations have been described in AD, how they correlate with the pathology is still unclear and represent an important area of research due to the potential therapeutic applications to improve neurogenesis. Besides the canonical role of nucleoporins (NUPs) as regulators of nucleus-cytoplasm trafficking, they have been recently discovered as important players in gene regulation in both health and disease. Specifically, Nup153, through the interaction with the transcription factor Sox2, maintains the stemness and responsiveness of adult neural stem cells regulating gene expression and epigenetic program.

Goals

We have recently found that the level of Nup153 in NSCs, from a mouse model of AD, is strongly diminished as well as its interaction with Sox2 determining their functional impairment and inefficient neurogenesis. The goal of our study will be to fully characterize Nup153 as potential new target in vivo in a mouse model of AD and to validate it in human samples taking advantage from iPSC-derived neurons and cortical organoids from control and AD patients using both 2D and 3D systems (organoids). By complementary integrated approaches (molecular analyses, electrophysiology, behavior) we expect: 1) to establish whether Nup153 modulation in vivo may recover inefficient neurogenesis and ameliorate cognitive and memory deficit in AD mice; 2) to validate Nup153 therapeutic potential in human cells.

Start date of activity

01/04/2019

Keywords

Alzheimer (AD), neurogenesis, nucleoporin

Last update: 10/05/2024