FTD-Organoids · Composition and dynamics of stress granules in cerebral organoid models of frontotemporal dementia
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-06-01 → 2022-05-31
- EU contribution
- €174,167
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Composition and dynamics of stress granules in cerebral organoid models of frontotemporal dementia
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.
Data: CORDIS, © European Union
Project objective
Frontotemporal dementia (FTD) is the second most common form of dementia. A pathological hallmark is the formation of protein aggregates that consist mainly of Tau or TDP43. Patients suffer from the degeneration of the frontal and temporal lobes with no effective treatments being available. The recent advancement of 3D brain organoid cultures grown from embryonic stem cells offer new possibilities to study disease mechanisms of neurological disorders and help validate therapeutic interventions. I therefore propose to generate the first cerebral organoid models of FTD. The new models will first be thoroughly characterized by immunohistochemical stainings and biochemical analysis. Furthermore, I will determine neuroaxonal degeneration, visualize protein aggregates and their cell-to-cell spreading and analyze the nucleation of the pathological protein conformation. In addition, I will determine if FTD-organoids recapitulate the brain region- and cell type-specific vulnerability that are observed in patients. FTD has also been linked to aberrant phase transition of proteins that can lead to disturbances in proteome and RNA homeostasis. However, molecular mechanisms and consequences of this processes in disease conditions remain largely unknown. I therefore propose to study the dynamics and molecular composition of stress granules, which are functional biomolecular condensates that arise through liquid-liquid phase separation during stress conditions, in FTD cerebral organoids. Disease-associated changes in stress granule dynamics and thus disturbances in RNA metabolism and regulation of neuronal translational might result in the lack of essential neuronal proteins. I will therefore identify and quantify key mRNA and protein components of neuronal stress granules in brain organoids. In summary, this project will provide new mechanistic insights into disease mechanisms of FTD and open new possibilities of therapeutic interventions.
Original text from CORDIS.
Participants
- INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH · WienCoordinatorAustria
Links
Data: CORDIS, © European Union