Researchers Explore Mechanisms Behind TDP-43 Clumping, Test Investigational Drug



A team of researchers has shown for the first time how toxic proteins produced by the mutated C9orf72 gene stimulate protein clumps that can result in the neurological decline associated with FTD, and point to an investigative drug that may reduce that buildup.

Led by researchers at Penn Medicine and Mayo Clinic, Jacksonville, FL, the pre-clinical study demonstrates how toxic proteins called poly(GR), produced by the mutated C9orf72 gene, stimulate the clumping of TDP-43, one of the proteins in the brain that form abnormal accumulations in FTD. Using a mouse model, researchers also showed that treatment with a pipeline drug known as antisense oligonucleotide (ASO) – which is still being tested and not approved for medical use – reduced the levels of the toxic poly(GR).

“A common genetic cause of ALS and FTD is a repeat expansion in the C9orf72 gene, which somehow leads to TDP-43 aggregation in degenerating neurons, but what remained unclear until now was how those two were connected,” said co-senior author James Shorter, PhD, of Penn Medicine, in a news release. “We found that TDP-43 aggregates much more rapidly if these toxic poly(GR) proteins are around, suggesting a direct link between the mutation, poly(GR), and TDP-43.”

After UPenn researchers demonstrated the role of poly(GR) proteins in TDP-43 accumulation, colleagues at Mayo Clinic, including Leonard Petrucelli, PhD, studied the interaction in both human cells and mice to support the initial findings. Their work showed poly(GR) as a driving mechanism behind TDP-43 accumulation in both the human cells and mice, providing further evidence of a connection between the two proteins. [In recent years, Dr. Petrucelli has received two awards from AFTD’s Biomarkers Initiative to study poly(GR).]

While still preliminary, the findings present the potential to explore new ways to treat FTD, ALS, and related neurological disorders, notably by targeting poly(GR) protein levels. Researchers plan to study in more detail how TDP-43 and poly(GR) and other similar toxic proteins associated with the mutated C9orf72 interact, and conduct further studies with ASO drugs to better understand their role in stopping the clumping of TDP-43.

“This exciting collaborative study sets the stage for continued teamwork in this space, which I see as being of great interest to the ALS and FTD community,” Shorter said in the release.

Click here to read more about the study.