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Selective mRNA Translation Control in Rodent Models Carrying Mutations in Genetic Autism Risk Factors

English title Selective mRNA Translation Control in Rodent Models Carrying Mutations in Genetic Autism Risk Factors
Applicant Scheiffele Peter
Number 200795
Funding scheme Project funding (Div. I-III)
Research institution Abteilung Zellbiologie Biozentrum Universität Basel
Institution of higher education University of Basel - BS
Main discipline Neurophysiology and Brain Research
Start/End 01.10.2021 - 30.09.2025
Approved amount 908'000.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Embryology, Developmental Biology

Keywords (4)

autism; rodent models; electrophysiology; cell biology

Lay Summary (German)

Lead
Analyse von Veränderungen in neuronaler Genexpression durch Genmutationen, welche mit Autismus assoziiert sind
Lay summary

 

Mit einer Inzidenz von etwa 1 in 100 betrifft Autismus eine beträchtliche Gruppe von Personen. Autismus ist ein Spektrum, in schweren Fällen, kann es zu deutlichen Beeinträchtigungen im täglichen Leben führen. Ziel dieses Projektes ist es Genmutationen, die mit schwere Formen von Autismus assoziiert sind, in Tiermodellen zu untersuchen, um deren Einfluss auf die Funktionen von neuronalen Netzwerken zu verstehen.  Insbesondere fokussiert sich diese Projekt auf den Einfluss auf die Kontrolle der mRNA Translation in Nervenzellen und deren Beitrag zum Sozialverhalten.

Direct link to Lay Summary Last update: 08.07.2021

Responsible applicant and co-applicants

Associated projects

Number Title Start Funding scheme
179432 Molecular mechanisms of neuronal synapse formation 01.08.2018 Project funding (Div. I-III)

Abstract

With an estimate incidence of 1 in 100 children, autism spectrum disorders represent an enormous burden on the population. These developmental disorders develop in the first years of life and to date no mechanism-based treatments are available to the patients. One of the most fundamental challenges in developing treatments for autism-spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of autism cases. Subsets of risk genes can be grouped into functionally-related pathways, most prominently synaptic proteins, translational regulation, and chromatin modifications. Recent work highlighted an unexpected convergence in pathophysiology between gene products contributing to seemingly distant cellular functions. Thus, findings from model organisms suggest that mutations in autism-associated synaptic components precipitate alterations in translational regulation which resemble dysfunctions emerging from direct genetic alterations in the mRNA translation machinery. Early work conceptualized translational de-regulation as representing “too high” or “too low” levels of translation. However, based on more recent evidence it is now hypothesized that alterations in translation machinery and cell signaling result in a selective translational de-regulation of specific mRNAs which are fundamental drivers of the pathophysiology of the disorders.In this project we propose to integrate experiments from the genome-wide dissection of neuronal mRNA translation programs to the cell- and circuit-specific assessments of the roles for selection mRNA translation control in rodent models of autism. In Aim 1, we will dissect the post-transcriptional regulation of oxytocin receptor mRNAs - a key regulator of social recognition and emotional behavior. In Aim 2, we will explore the role for eIF3g, a translation initiation factor encoded by an autism risk gene, in selective neuronal mRNA translation and neuronal function. Ultimately, this work will advance two novel concepts about the post-transcriptional control in models of autism: the impact of upstream open reading frames on the translational regulation of oxytocin receptors and a genome-wide analysis of selective mRNA translation regulation dependent on the translation initiation factor eIF3g. Insights into these molecular mechanisms, in particular, the translational regulation of oxytocin receptors might prove valuable for the development of novel therapeutic approaches targeted to modify the translational output of this critical regulator of social behaviors in disease states.
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