2023 Alzheimer's Association Clinician Scientist Fellowship (AACSF)
The Role of Sulfation for cellular Tau pathology in vivo
Can limiting specific modifications of heparan sulfate proteoglycans prevent cell-to-cell spread of tau aggregates?
Barbara Stopschinski, M.D.
University of Texas Southwestern Medical Center
Dallas, TX - United States
Background
Tau is a protein that helps to maintain the structure of brain cells. In Alzheimer’s and other brain diseases, the shape of tau protein becomes modified or “misfolded,” a change that may contribute to tau tangles (a hallmark of these diseases) and subsequent nerve cell damage. However, the biological mechanism behind how tau moves through the brain is not fully understood. One of the suggested models is that pieces of the tau can be released from the initial nerve cell and then is taken up by nearby cells. It is proposed that these pieces then act as seeds for further tangles to develop in new cells.
Normally, cells only allow the entry of specific molecules to limit the potential damage to the cell. Stopschinski and colleagues have shown that these tau fragments bind to heparan sulfate proteoglycans (HSPGs), which are modified proteins found on the exterior of nerve cells. This binding then triggers the uptake of the tau pieces into the cell. They have also identified a number of modifications to HSPGs including the addition of a sulfate group (a chemical modification) to HSPGs. In this project, they plan to limit the sulfotransferase activity on the HSPGs and determine the effect on the spread of tau between cells. Stopschinski aims to identify specific ways to prevent that binding and the resulting uptake, thus limiting the spread of tau tangles from cell to cell.
Research Plan
Stopschinski and colleagues will develop miRNA, or microRNAs, against each different sulfotransferase in order to determine which are most critical to tau binding. miRNAs are small molecules that help determine what genes are turned “off” and “on” before proteins are made. By using miRNAs, researchers can limit the amount of the sulfotransferases made in a cell.
The miRNAs will then be injected into the brains of genetically-engineered Alzheimer’s like mice that develop increased levels of tau. They will then determine if reducing the sulfotransferases using miRNAs were effective in limiting the spread and development of further tau tangles. They will also perform a test to understand how tau spreads through the brain of the mice.
Impact
This project has the potential to help determine the model of tau tangle spread in the brain. Further, it also has the potential to identify numerous targets that could be utilized for the development of drugs that could limit the spread of tau in Alzheimer’s.