ALS researchers at Gladstone, Michigan shed new light on a key drug target

Brain cell with TDP43 and hUPF1 highlighted.--Courtesy of Sami Barmada

Building on earlier research work, a team of investigators from the Gladstone Institutes and the University of Michigan say they can shed new light on a prime target and pathway that could be critical to developing a new drug for ALS.

It's already known that elevated levels of the protein TDP43 can be toxic to cells and that another protein, hUPF1, could prove a valuable drug target for investigators. This team found that if you genetically increase levels of hUPF1, you could control TDP43 and increase neuron survival by 50% to 60%. And they add that the body regulates hUPF1 action through a pathway dubbed nonsense mediated decay, or NMD.

The role of NMD, they add, is to scan for defective messenger RNA and destroy it before it spawns dysfunctional proteins. The protein hUPF1 is a "master regulator" of NMD, which in turn monitors TDP43 in order to manage the body's natural machinery for splicing.

Steven Finkbeiner

Steven Finkbeiner, a senior investigator at the Gladstone Institute of Neurological Disease, says this is the first time that the role of NMD has been illuminated in handling neurodegerative disease, making it an important field in both ALS research as well as frototemporal dementia, which shares many of the same proteins.

"TDP43 is a 'Goldilocks' protein: too much, or too little, can cause cellular damage," says first author Sami Barmada, an assistant professor of neurology at the University of Michigan Medical School. "Over 90% of ALS cases exhibit TDP43-based pathology, so developing a treatment that keeps protein levels just right is imperative."

Now the team plans to develop a drug that can target the NMD pathway and regulate TDP43 in hopes of treating ALS, a lethal condition that paralyzes its victims and then kills them.

- here's the release