Skip to main content
European Commission logo print header

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

Project description

An in vitro 3D model of dementia

Patients suffering from frontotemporal dementia (FTD) present with degeneration in the frontal and temporal lobes of the brain associated with the formation of protein aggregates. Given the lack of FTD treatments today, the EU-funded FTD-Organoids project will employ 3D brain organoid cultures grown from embryonic stem cells as the first in vitro cerebral model of FTD. Scientists will characterise this model at the cellular and molecular level and investigate the mechanisms underlying FTD pathophysiology. The project's results have the potential to identify novel FTD targets for the development of therapeutic interventions.

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.

Coordinator

INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH
Net EU contribution
€ 174 167,04
Address
Dr bohrgasse 3
1030 Wien
Austria

See on map

Region
Ostösterreich Wien Wien
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Links
Other funding
€ 0,00