Explanation for Protein Clumps in Autopsy Brain Cells of ALS Patients

In an estimated 97 percent of people with amyotrophic lateral sclerosis (ALS) and 45 percent of those with one form of dementia, the protein TDP-43 clumps inside brain or nerve cells.

Scientists didn’t know the precise role of TDP-43 or the consequences of the clumping. Now, researchers have found that normally, TDP-43 prevents cells from using unwanted genetic information called cryptic exons to make proteins.

Scientists deleted the gene for TDP-43 from both lab-grown mouse and human cells and detected abnormal processing of strands of RNA. 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 the authors 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.

"We've explained what happens after TDP-43 is lost, but we still don't know why it aggregates in the first place," author says.

http://www.hopkinsmedicine.org/…/scientists_report_explanat…