2023 Alzheimer's Association Research Grant (AARG)

Detecting TDP-43 Cryptic Exons Across Cell Types and Brain Regions in AD

How does the build-up of proteins in the brain impact Alzheimer’s and other brain diseases?

Jonathan Ling, Ph.D.
Johns Hopkins University School of Medicine
Baltimore, MD - 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 frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease). Additionally, about half of the individuals with Alzheimer’s have abnormal build-up of TDP-43 in their brains. Studies have shown that increases in TDP-43 may be connected to brain shrinkage due to nerve cell death and contribute to accelerated cognitive decline in individuals with Alzheimer’s. The mechanisms by which the TDP-43 protein contributes to brain changes associated with Alzheimer’s are not yet fully understood.

Each cell in the human body has a highly specific machinery to make proteins, which perform different cellular functions. In order to make a protein, pieces of DNA are copied into another type of genetic material called ribonucleic acid (RNA). RNA is responsible for “reading” DNA instructions for making proteins. 

Dr. Ling and colleagues recently found that TDP-43 is typically responsible for keeping abnormal areas of RNA called “cryptic exons” from being used by nerve cells to make proteins. Cryptic exons are usually blocked by cells from becoming part of the final RNA used to make a protein. However, when TDP-43 clumps inside the nerve cells, it malfunctions and can’t do its job. This results in the cells using cryptic exons to make abnormal proteins, causing a cascade of events leading to nerve cell death.

Research Plan

Dr. Ling and colleagues developed a new technique of identifying the components that make up a molecule of RNA (RNA sequencing) that will allow them to study cryptic exons across brain cell types and brain regions. This new technique is called TaCO single nuclei RNA sequencing. 

The research team will study brain samples from individuals who had Alzheimer’s with TDP-43 clumping and those who had Alzheimer’s without TDP-43 clumping. They will use the TaCO technique to identify cryptic exons in different types of brain cells as well as in various brain regions.

Impact

This project will study a new method of RNA sequencing that may help researchers learn more about how different proteins impact Alzheimer’s. The findings may contribute to the understanding of the role of TDP-43 in Alzheimer’s and other brain diseases.