Scientists Identify New Drug Target To Treat ALS

Scientists identify new drug target to treat ALS
Brain cell with TDP43 and hUPF1. Blue is the nucleus,
cyan is hUPF1, green is TDP43, red is the cell body in
this image. (Credit: Sami Barmada)
Scientists have identified a cellular mechanism that can be targeted to treat ALS. The researchers revealed that increasing levels of a certain key protein successfully protected against cell death in both genetic and sporadic versions of the disease. What's more, treating this pathway may also have implications for frontotemporal dementia because many of the same proteins are involved. The research was published in the journal PNAS.
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a debilitating neurodegenerative disorder that leads to paralysis and death due to the loss of motor neurons in the brain and spinal cord. A primary feature of ALS is an accumulation of the protein TDP43, too much of which is toxic to cells. In the current study, the researchers identified another protein, hUPF1, that keeps TDP43 in check, thereby preventing cell death.
Previous investigations had identified hUPF1 as a potential therapeutic target for ALS, but it was unclear how this protein prevented cell death. In the current study, the scientists tested hUPF1's ability to protect against neurodegeneration using a cellular model of ALS. They discovered that genetically increasing levels of hUPF1 extended neuron survival by 50-60%. Digging deeper, the researchers revealed that hUPF1 acts through a cellular surveillance system called nonsense mediated decay, or NMD, to keep TDP43 levels stable and enhance neuronal survival.
This protective mechanism (NMD) monitors messenger RNA (mRNA). If a piece of mRNA is found to be defective, it is destroyed so that it cannot go on to produce dysfunctional proteins that can harm the cell. It now appears that NMD also helps control the levels of proteins, like TDP43, that bind to RNA and regulate splicing. Since hUPF1 is a master regulator of NMD, altering it has a trickle-down effect on TDP43 and other related proteins.
The scientists say the next step is to develop a drug that can target NMD - by manipulating hUPF1 or through other proteins that affect this system - to influence levels of TDP43 and protect neurons.
Based on material originally posted by Gladstone Institutes.