Insights into the behavior of TDP-43 — a key protein in amyotrophic lateral sclerosis (ALS) development — may offer clues in preventing protein aggregation, potentially leading to new treatments for the disease.
And the new level of understanding of how the protein is controlled and what it does in the cell may also bring scientists closer to understanding why ALS appears in the first place.
TDP-43 is a protein that acts to process RNA in the cells. In its normal state, it needs to accumulate to perform these processes and keep cells alive. But too much accumulation leads to disease.
The research team at Saint Louis University wanted to learn more about the processes that balance the aggregation, preventing it from going too far.
“Most of us go around with our TDP-43 working well. When does it not work well? What are those conditions? And, what are the really important functions of TDP-43 that happen in cells, functions that would cause the degeneration of neurons without them?” Yuna Ayala, PhD, assistant professor of biochemistry and molecular biology, said in a press release.
To do this, they focused their efforts on a process called phosphorylation. This is one of the most common methods cells use to control various processes. Virtually, certain enzymes add chemical phosphor molecules to proteins to change their behavior.
They found that a specific enzyme, called MEK, adds two phosphor molecules to the TDP-43 protein when cells are exposed to heat stress. They noted that in conditions normally triggering misfolding of proteins, the phospho-tagged TDP-43 did not aggregate, suggesting that they had identified a protective mechanism.
The tagging also made the protein travel to a cell compartment previously not linked to TDP-43 actions.
“Now we want to understand what it is doing in this compartment, its specific function, and how that translates to ALS and dementia,” Ayala said.
She believes that the new findings may lead researchers on a path where new drug discoveries may become possible.
“We may be able to use that kinase pathway as a target to develop drugs that will make TDP-43 happier, preventing disease and preventing the aggregation of other proteins,” she said.
“So I think this work will really help us understand what leads to the development of ALS and dementia, to help us know the principle causes of neurotoxicity in these cells. It may help us test therapies against the disease and adapt some of the drugs that are already available,” Ayala added.
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