Researchers are beginning to fill in the missing pieces and gain a better understanding of diseases like ALS and frontotemporal dementia (FTD).
A research team from the University of Michigan has zeroed in on the TDP-43 proteins as a target to stop the progression of nerve cell destruction in people suffering from neurobiological diseases.
It has long been known that the TDP-43 protein accumulates in the nerve cells of those with neurobiological diseases, causing the nerve cells to ultimately die. However, scientists did not previously know why this protein causes so much destruction.
In the study, the researchers found a structure within the TDP-43 protein that is critical for the function and ability of the protein to cause nerve cell death, and uncovered possible hints that could lead to techniques that save the nerve cells from death.
“By manipulating the structure of the protein, we determined that RNA binding is pivotal for maintaining the stability, function and toxicity of TDP-43 in disease models,” Michigan Medicine’s Sami Barmada, MD, PhD, an assistant professor of neurology, said in a statement.
For healthy people, TDP-43 helps to regulate both the processing and stability of RNA. However, the researchers found that too much of the protein destabilizes RNA, affecting both energy and protein production, two pathways required for nerve cells to survive.
The researchers discovered identical patterns in ALS patients, which indicates that the TDP-43 protein is responsible. To confirm this result, the researchers focused on manipulating the function of the protein by changing its structure.
They opted to introduce specific mutation to interrupt an interaction between two parts of the protein needed for RNA binding. This results in versions to the protein that are unable to bind to RNA. One unexpected result of this is that the protein quickly degrades when it cannot bind RNA, resulting in a version of TDP-43 that may not be as dangerous for nerve cells.
The researchers then used a method called automated microscopy to determine the overall danger by producing thousands of nerve cells in cultures that are imaged over time using a microscope controlled by programs. They were able to use additional programs to determine when each cell dies and compared the data to data under different conditions using methods from human clinical trials.
“This is like a clinical trial in a dish, measuring the fate of each nerve cell as if it were a person,” Barmada said. “We saw when we interrupted the structure, it dramatically destabilized the protein. Cells just chewed it up. We know in disease that if there is too much TDP-43, cells die. If the excess TDP-43 is degraded, as here, the cells are rescued.”
They then created a worm model of the protein with the same structural changes using CRISPR/Cas9 genetic editing tools and found that worms expressing these versions of TDP-43 were identical to worms with no TDP-43 at all. This suggests that the structure targeted by the mutations is needed for the protein’s function and toxicity.
The researchers believe they can harness this discovery and eventually develop a drug that would interact with TDP-43, interfere with its structure and cause it to be degraded.
“If you have an approach that can interrupt this structure, you might be able to mop up the extra TDP-43 that’s there and prevent nerve cell death,” Barmada said.
The study was published in Cell Reports.
Filed Under: Neurological Disease
