In a recent paper published in The Journal of Biological Chemistry Yuna Ayala, PhD, assistant professor of biochemistry and molecular biology at Saint Louis University, and her research team made advances in understanding how a protein causes damaging plaques to build up in neurodegenerative illnesses like amyotrophic lateral sclerosis (ALS) and a form of dementia called frontotemporal lobar degeneration.
Ayala and her lab study TDP–43, a protein that binds to RNA and plays a role in gene expression. In 2006, researchers discovered that TDP–43 was the main feature of neurological disorders like ALS and frontotemporal dementia.

TDP–43 is an important protein tied to cell survival, metabolism and function that has been conserved by evolution in animals from flies to humans. Without TDP–43, scientists see animals develop locomotive defects and shortened lifespans. Mice that lack this protein do not survive beyond the embryonic stage. It regulates many genes and controls the processing of messenger RNA.

When TDP–43 builds up in cells, it causes damaging plaque to accumulate; this is a hallmark of ALS and frontotemporal lobar degeneration. It also is present in other types of neurodegenerative diseases, including Alzheimer's disease. In addition to ALS, TDP–43 is found in cases of frontotemporal dementia, a type of dementia that is distinct from Alzheimer’s disease. Where Alzheimer’s patients develop memory problems, those with frontotemporal dementia lose inhibition and undergo a gradual decline in behavioral and speaking ability.

TDP–43 also is tied to minor neurodegenerative disorders and, in a recent discovery, is present in many Alzheimer’s disease patients, as well. While the connection to Alzheimer’s is not yet understood, scientists speculate that TDP–43 may be a secondary pathology or a marker of Alzheimer’s disease.

Among all of these neurodegenerative disorders is a common factor: they are characterized by the irreversible accumulation of plaques. A protein or set of proteins aggregates, causing plaque to build up. And, scientists know that in ALS and frontotemporal dementia, the aggregating protein is TDP–43.

The SLU team decided to see if phosphorylation – one of the most common ways that proteins are regulated – may be responsible for managing the activity, location and how tightly the protein binds. Scientists know that when they stress cells in a certain way, they activate a heat shock response, triggering phosphorylation. Ayala used this procedure to see if phosphorylation was involved with TDP–43’s actions.

“Heat shock response is the first stress conditions that will alter cell metabolism that was ever discovered, and it is found in organisms ranging from yeast to humans. The idea is that when you increase the temperature of the cells, the cells have a response that is similar across many creatures. That is the signal that triggers many cellular changes including phosphorylation of some proteins.

Ayala and her team found that this kinase, MEK, phosphorylates at two residues.

Next, the researchers wanted to know if phosphorylation was affecting protein functions, and they found that it regulates the ability to control processing.

“It made TDP–43 go to a compartment where it hadn’t previously been,” Ayala said. “It may be involved in regulating a type of RNA we didn’t know it regulated and it may be very important for cellular metabolism.

“Now we want to understand what it is doing in this compartment, its specific function and how that translates to ALS and dementia.”