In a new study published in The Journal of Biological Chemistry, researchers report advances in the understanding of how the protein TDP-43 causes damaging plaques to build up in neurodegenerative illnesses like amyotrophic lateral sclerosis (ALS) and a form of dementia called frontotemporal lobar degeneration. 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, however, 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 is also tied to other neurodegenerative disorders and was recently shown to be 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 researchers aimed to learn more about how TDP-43 works within cells and is regulated. Their first question was a matter of balance. TDP-43 is an indispensable protein that needs to accumulate in order for vital cell processes to occur. Too much, though, and the protein aggregation causes plaques to build up.
The 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. The researchers used this procedure to see if phosphorylation was involved with TDP-43’s actions, and found that the 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, causing TDP-43 to go to an area where it wasn’t previously.
Paper: “Heat Shock-induced Phosphorylation of TAR DNA-binding Protein 43 (TDP-43) by MAPK/ERK Kinase Regulates TDP-43 Function”
Reprinted from materials provided by Saint Louis University.