Researchers Hone in on Frontotemporal Dementia Cause and Cure

A new study finds that toxic proteins from a mutated gene stimulate the clumping of TDP-43, the protein thought to cause FTD and ALS

Build-up of a protein called TDP-43 that form in the brain are a well-known biomarker of ALS, also known as Lou Gehrig’s disease, and frontotemporal dementia, or FTD. New research from Penn Medicine and Mayo Clinic offers new insight into how TDP-43 clumps form, and how to stop them.

The new pre-clinical study published in Science Translational Medicine shows for the first time how certain toxic proteins lead to the clumping of TDP-43. The toxic proteins, called poly(GR) (glycine-arginine repeat), are produced by a mutated gene called C9orf72.

In a mouse model, the researchers also show that treatment with an experimental drug, antisense oligonucleotide (ASO), reduced the levels of these proteins and so reduced the damaging protein clumps and the neurodegeneration that comes along with them.

More Data About the Causes of Lou Gehrig’s Disease and Frontotemporal Dementia

“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,” co-senior author James Shorter, PhD, a professor of Biochemistry and Biophysics in the Perelman School of Medicine at the University of Pennsylvania, said in a news statement. “But what remained unclear until now was how those two were connected.”

Shorter’s team found a clue: a relationship between the genetic risk factor gene, the biomarker TDP-43, and these certain toxic proteins.

“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,” he said.

Dr. Hana Odeh, a post-doctoral fellow in the Shorter lab and co-first author, added: “This finding presents an exciting potential therapeutic target to treat these debilitating diseases by lowering poly(GR) levels.”

After Shorter’s team demonstrated the role of poly(GR) proteins in TDP-43 accumulation at the protein level, their colleagues at Mayo Clinic in Jacksonville, Fla., explored the interactions in a mouse study as well as in human cells. The same relationship discovered at Penn emerged in the Mayo lab’s research: Poly(GR) can corner TDP-43 proteins in human cells, thus bringing on the formation of the dense protein clumps that are a biomarker for ALS and FTD.

In addition to observing this relationship in human cells, the Mayo researchers also observed it in a mouse model.

Past studies have also shown this link between both TDP-43 and poly(GR) and neurodegeneration in human patients. According to the researchers, the higher the protein levels, the worse the neurological function, providing further evidence that the two proteins are conspiring.

Experimental Drug c9ASO Appears to Reduce the Protein Clumping That Leads to ALS and FTD

Next, the team delivered an ASO drug known as c9ASO, which is being investigated in clinical trials, into the brains of three-month old mice expressing the ALS/FTD-causing repeat-expansion. They found the drug diminished the presence of the toxic protein poly(GR) and the clumps of protein TDP-43.

The experimental drug, c9ASO, appeared to switch off the mutations of the problem gene C9orf72 which seems to put this cascade of events into effect. Past research has observed this and linked this deactivation of the gene to lower levels of poly(GR), but the Penn and Mayo Clinic teams’ research is the first time scientists have also been able to see that the ALS and FTD biomarker of TDP-43 clumping was also reduced.

Next steps for the researcher team includes further study of how TDP-43, poly(GR) and similar toxic proteins linked to the mutated C9orf72 gene interact. They will also conduct further studies with ASO drugs to better understand how they might stop the clumping of TDP-43 and thereby help prevent or reverse neurological conditions like FTD and ALS.

“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.