2024 Alzheimer's Association Research Fellowship (AARF)

Engineering importins to counter TDP-43 pathology in Alzheimer's Disease

Can directing abnormally accumulated proteins to the cell’s nucleus be a therapeutic strategy for treating Alzheimer’s?

Miriam Linsenmeier, Ph.D.
The Trustees of the University of Pennsylvania
Philadelphia, PA - United States

Background

Abnormal build-up of the protein TAR DNA-binding protein 43 (TDP-43) in the brain is a hallmark of many brain diseases, including Alzheimer’s and other dementias such as frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). Studies have shown that about half of individuals with Alzheimer’s have elevated levels of TDP-43 in their brains and increases in TDP-43 may be linked to brain shrinkage and cognitive decline. However, the mechanisms by which TDP-43 contributes to cognitive decline in Alzheimer’s are unknown.

In healthy brain cells, TDP-43 is present and functional in the nucleus (the control center of the cell), while in Alzheimer’s and other brain diseases, TDP-43 is present in the cytoplasm (the open, fluid-filled space inside a cell) where it accumulates in harmful clumps. Dr. Miriam Linsenmeier and colleagues hypothesize that redirecting TDP-43 into the nucleus may be a viable therapeutic approach to reverse TDP-43 build-up and slow cognitive decline in Alzheimer’s. 

Research Plan

For their studies, Dr. Linsenmeier and the team will evaluate whether Importin (IPO-13), which is a protein that can physically interact with other proteins in the cell and direct them towards the nucleus, can guide harmful TDP-43 aggregates to the nucleus in Alzheimer’s. They will do this by first identifying the specific regions of IPO-13 and TDP-43 that physically interact and generating a specific form of IPO-13 that will bind to TDP-43 and not bind to other essential proteins in the cytoplasm of brain cells. The researchers will then use human nerve cells grown in a laboratory dish to evaluate whether the IPO-13 variant can direct accumulated TDP-43 from the cytoplasm to the nucleus.

Impact

This project may identify a new potential therapeutic strategy to prevent or reverse the accumulation of TDP-43 aggregates in the brain. If successful, the results may also support future research into the use of Importins for the treatment of Alzheimer’s and other dementias.