Scientists have of late been making progress in understanding the role of TDP-43 accumulation in the nerve cell degeneration and death that characterizes amyotrophic lateral sclerosis (ALS) and some forms of frontotemporal dementia (FTD). Potential drug targets have emerged that may allow better clearing of unwanted TDP-43 through cellular quality control mechanisms, for example. The researchers quoted here have a different approach in mind, however, focusing on the use of other proteins that can perform the vital cellular functions that are disrupted when too much TDP-43 is present, but which are not themselves affected by high levels of TDP-43:
TDP-43 is normally responsible for keeping unwanted stretches of the genetic material RNA, called cryptic exons, from being used by nerve cells to make proteins. When TDP-43 bunches up inside those cells, it malfunctions, lifting the brakes on cryptic exons and causing a cascade of events that kills brain or spinal cord cells. Researchers deleted the gene for TDP-43 from both lab-grown mouse and human cells and detected abnormal processing of strands of RNA, genetic material responsible for coding and decoding DNA blueprint instructions for making proteins. Specifically, they found that cryptic exons - segments of RNA usually blocked by cells from becoming part of the final RNA used to make a protein - were in fact working as blueprints. With the cryptic exons included rather than blocked, proteins involved in key processes in the studied cells were abnormal.
When the researchers studied brain autopsies from patients with ALS and FTD, they confirmed that not only were there buildups of TDP-43, but also cryptic exons in the degenerated brain cells. In the brains of healthy people, however, they saw no cryptic exons. This finding, the investigators say, suggests that when TDP-43 is clumped together, it no longer works, causing cells to function abnormally as though there's no TDP-43 at all. TDP-43 only recognizes one particular class of cryptic exon, but other proteins can block many types of exons, so researchers next tested what would happen when they added one of these blocking proteins to directly target cryptic exons in cells missing TDP-43. Indeed, adding this protein allowed cells to block cryptic exons and remain disease-free. "What's thought provoking is that we may soon be able to fix this in patients who have lots of accumulated TDP-43."