2023 Endolysosomal Activity in Alzheimer’s (E2A)
An iPSC-based toolbox to investigate endolysosomal mechanisms in FTD-GRN
How can a new laboratory method be used to study protein accumulation in brain diseases?
Dominik Paquet, Ph.D.
LMU University Hospital Munich
Munich, Germany
Background
Abnormal accumulation of the protein TAR DNA-binding protein 43 (TDP-43) in the brain is a hallmark of many brain diseases, including frontotemporal dementia (FTD). FTD refers to a group of degenerative diseases characterized by progressive nerve cell loss in the brain’s frontal lobes (areas behind your forehead) or temporal lobes (regions behind your ears). Studies have shown that accumulation of TDP-43 may contribute to accelerated cognitive decline in individuals with FTD. However, the mechanisms by which the TDP-43 protein contributes to brain changes associated with FTD are not yet fully understood.
Dr. Dominik Paquet and colleagues believe that variations in a specific gene called GRN may contribute to TDP-43 accumulation in the brain and have developed a method to potentially study how mutations in GRN lead to TDP-43 accumulation in FTD.
Research Plan
Dr. Paquet and the team will develop a new tool that uses a specialized type of stem cell from adults and grown in a laboratory dish called induced pluripotent stem cells (iPSCs) which can be “programmed” to develop into any type of cell in the human body. They will program these cells into microglia, the brain’s primary immune cells, and use gene editing technology to turn “off” GRN. Then the researchers will grow these cells as organoids, or three-dimensional brain structures grown in a laboratory dish. Next, Dr. Paquet and the team will use these tools to study how microglia with variations of GRN are able to help remove accumulated TDP-43 from other type of brain cells grown in the same laboratory dish.
Impact
This project may develop a new method to help researchers study the association between TDP-43 and FTD. If successful, the findings may contribute to our understanding TDP-43’s role in FTD and other brain diseases.