2021 Alzheimer's Association Research Fellowship (AARF)

Strategies to Prevent TDP-43 Aggregation and Dipeptide-Repeat Toxicity in FTD

What are the biological mechanisms by which abnormal protein accumulation happens in the brain in frontotemporal dementia?

Hana Odeh, Ph.D.
University of Pennsylvania
Philadelphia, PA - United States

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) and sometimes Alzheimer’s. Studies have shown that TDP-43 accumulation may be associated with brain shrinkage and cognitive decline in people with Alzheimer’s, but the biological mechanisms by which TDP-43 may impact brain changes in Alzheimer’s and other dementia are not yet understood. 

Previous research has shown that a change in a specific gene called C9ORF72 may be associated with brain changes observed in FTD. The C9ORF72 gene helps nerve cells communicate with each other. Studies show that the genetic changes in C9ORF72 may trigger the production of proteins called dipeptide repeats (DPRs). The DPRs are thought to interact with TDP-43, although the biological mechanism underlying this interaction is unknown. Dr. Hana Odeh believes that this interaction may be associated with the accumulation of TDP-43 in the brain.

Research Plan

Dr. Odeh and colleagues will use several biochemical approaches to study in detail the interactions between TDP-43 and DPRs that may be associated with the accumulation of TDP-43. The researchers will also study the interactions between TDP-43 and DPRs in genetically engineered Alzheimer’s-like mice. Dr. Odeh believes that an understanding of the biology by which how DPRs interact with TDP-43 could shed light on how this interaction could impact brain changes in FTD and other brain diseases.

Impact

The results of this project could help uncover the biology of how TDP-43 accumulates in the brains of people with FTD and other dementia. If successful, this work could contribute to the development of potential therapeutic strategies to prevent the accumulation of TDP-43 in FTD, Alzheimer’s, and other neurodegenerative diseases.