Identification of Receptors for TDP-43 That Mediate Cellular Uptake and Neurotoxicity
Abstract
This proposal directly addresses the FY20 PRMRP Topic Area of Frontotemporal Degeneration. Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease that typically strikes in late adulthood. FTLD patients commonly present with changes in their behavior and personality, with a loss of social awareness and an inability to control impulses. Many neurodegenerative diseases are caused by the change in three-dimensional shape, or fold, of a normal protein into a pathological, disease-causing shape. These disease-associated shapes form aggregates, which lead to neuronal death. In recent years, it has been appreciated that this change occurs through a self-templated mechanism. That is, the shape of the normal protein is corrupted to the pathological shape through a direct interaction between the two; this process is responsible for the propagation of the pathological shape throughout the brain. Evidence suggests that this process occurs with aggregates of a protein called TDP-43, which is found in many cases of FTLD. These new findings raise a number of questions: 1) How do TDP-43 aggregates, which are found inside the cell, enter from the outside to come into contact with the normally folded version? 2) Does this play a role in the toxicity of these aggregates? The first question will be addressed by systematically lowering the amount of every protein on the cell surface using sophisticated genetic technology and then measuring the amount of TDP-43 aggregates that can enter the cell. A second approach uses a novel method to label everything in the vicinity of TDP-43 aggregates with a tag to determine their identity. Human neurons grown from adult stem cells will then be used to determine the role of candidate interactors in the toxicity caused by TDP-43 isolated from the brains of FTLD patients. Because nothing is known about cellular receptors for TDP-43 aggregates, it is expected that findings from these studies will open the door to new avenues of research and identify targets that can be used to create therapies for this currently untreatable disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110141
Entities
People
- Robert Mercer
Organizations
- Boston University Medical Campus
- United States Army