Composition and dynamics of stress granules in cerebral organoid models of frontotemporal dementia

Project Information

FTD-Organoids

Grant agreement ID: 897137

DOI

10.3030/897137

Project closed

EC signature date 6 May 2020

Start date 1 June 2020

End date 31 May 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 174 167,04

EU contribution

€ 174 167,04

Coordinated by

INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH
Austria

Periodic Reporting for period 1 - FTD-Organoids (Composition and dynamics of stress granules in cerebral organoid models of frontotemporal dementia)

Reporting period: 2020-06-01 to 2022-05-31

Summary of the context and overall objectives of the project

This project aimed to study temporal and post-transcriptional gene expression during the development of the human cerebral cortex, which is a highly elaborate process occurring over several months. Studies using mouse model systems, human fetal samples as well as brain organoids have revealed elaborate gene regulatory networks that orchestrate mammalian corticogenesis. However, an emerging theme from mouse studies highlights additional roles of post-transcriptional gene regulatory mechanisms. Whether similar mechanisms play a role in human neurodevelopment remains elusive. Fully understanding gene regulation during human brain development is of critical importance to understand the causes of neurodevelopment disorders, such as autism spectrum disorder (ASD) or intellectual developmental disorder as there are currently no known cures available.
Hence, the overall objective was to investigate the post-transcriptional control of gene expression and protein abundance to comprehensively understand gene regulation during human brain neurodevelopment.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

For this project, neural progenitors and neurons from telencephalic brain organoid tissues were isolated at different developmental stages, followed by transcriptome and proteome analysis to study post-transcriptional mechanisms of gene expression. Finally, bioinformatic analysis revealed temporal modules of gene expression during neural progenitor proliferation and subsequent neurogenesis in the developing telencephalic brain organoid tissue.
The integrated OMICS data has been made available to the general public in a searchable format accessible from the following website: https://shiny.knoblich.vbc.ac.at/
Additionally, the data has been submitted to a journal for peer-reviewed, open access publication and uploaded to a bioRxiv preprint server (https://www.biorxiv.org/content/10.1101/2022.10.07.511280v1) for immediate access. Social media posts (Twitter: https://twitter.com/knoblich_lab) were used to increase visibility of the research and a press release will be issued once the manuscript has been accepted for publication in a peer reviewed journal. The results will furthermore be presented to the scientific community at the "Development and 3D Modeling of the Human Brain" conference in Cold Spring Harbor from December 7th-10th, 2022.
All raw RNA-seq data are accessible via the accession number GSE214654 from https://www.ncbi.nlm.nih.gov/geo/ and raw proteomics data via the accession PXD037106 from https://www.ebi.ac.uk/pride/ which will increase reproducibility of the data. All dissemination and communication actions were done at no additional costs.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

When the brain does not develop normally, the disabilities that ensue can affect a person for life. Such neurodevelopmental disorders often occur as a result of genetic mutations, with many genes identified appearing to encode proteins that are involved in protein synthesis and gene regulatory pathways. While most studies have focused to understand transcriptional and epigentic differences, this study focused on the post-transcriptional regulation of gene expression during corticogenesis. Understanding such basic principles of neurodevelopment will help to develop mechanism-based therapeutics for these disorders.

Schematic overview of the cell sorting and multiOMICs approach from dorsal telencephalon organoids.