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Researchers identify previously unknown neuroprotective pathway in ALS.

Scientists from the Gladstone Institutes and the University of Michigan have identified a cellular mechanism that can be targeted to treat ALS. The researchers discovered 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.

Previous studies show that 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.  The team state that TDP43 is a ‘Goldilocks’ protein, in that too much, or too little, can cause cellular damage.  They go on to add that over 90% of ALS cases exhibit TDP43-based pathology, so developing a treatment that keeps protein levels just right is imperative.  The study is published in the journal PNAS.

Previous studies had identified hUPF1 as a potential therapeutic target for ALS, however, 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. The data findings showed 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 to keep TDP43 levels stable and enhance neuronal survival.

The team explain that this protective mechanism, nonsense mediated decay, 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. Results of the current study show that nonsense mediated decay also helps control the levels of proteins, like TDP43, that bind to RNA and regulate splicing. Since hUPF1 is a master regulator of nonsense mediated decay, altering it has a trickle-down effect on TDP43 and other related proteins.

The researchers state that cells have developed a elegant way to maintain homeostasis and protect themselves from faulty proteins.  They go on to add that this is the first time this natural monitoring system has been linked to neurodegenerative disease. They surmise that leveraging this system could be a strategic therapeutic target for diseases like ALS and frontotemporal dementia.

The team say that the next step is to develop a drug that can target nonsense mediated decay by manipulating hUPF1 or through other proteins that affect this system, to influence levels of TDP43 and protect neurons.

Source:  Gladstone Institutes


Cell with TDP43 and hUFP1.  Blue is the nucleus, cyan is hUPF1, green is TDP43, red is the cell body in this image.  Credit:  Sami Barmada.
Cell with TDP43 and hUFP1. Blue is the nucleus, cyan is hUPF1, green is TDP43, red is the cell body in this image. Credit: Sami Barmada.

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